In 1515 Bucer studied theology in the Dominican monastery in Heidelberg and the following year he took a course in dogmatics in Mainz where he was ordained a priest. In January 1517 he returned to Heidelberg where he enrolled in the university. An inventory of his books made in 1518 showed that he owned all of the important works of Thomas Aquinas, the leader of medieval scholasticism within the Dominican order. At the same time, Bucer became increasingly influenced by humanism and he started to purchase books from Johannes Froben, the publisher of the great humanist, Erasmus. In April 1518, Johannes von Staupitz, the vicar-general of the Augustinians, invited the Wittenberg reformer, Martin Luther to present his theology at the Heidelberg Disputation. It was on this occasion that Bucer met Luther for the first time. In a long letter to his mentor, Beatus Rhenanus, he recounted on what he learned and commented on several of Luther's Ninety-Five Theses. Bucer largely agreed with Luther and he was pleased with the far-reaching agreement he perceived between the ideas of Luther and Erasmus. However, Bucer also clearly understood the implications of his encounter with Luther and he asked Rhenanus to not let his letter fall into the wrong hands. Sensing the potential danger, Bucer formally wrote his will in the form of the previously mentioned inventory of all his books.
By early 1519, Bucer received the degree of baccalaureus biblicus. In the summer of that year, he publicly expressed his theological views for the first time in a disputation before the faculty. His theses revealed his first break with Aquinas and scholasticism. When he read Luther's commentary on Galatians, he was pleased to find that his own views were in agreement with Luther's developing theology. While he wrestled with the new thoughts and ideas, turmoil in secular and ecclesiastical politics were brewing that would eventually force him to abandon the Dominican order. The grand inquisitor of Cologne and Dominican, Jacob van Hoogstraaten, had decided to prosecute Johann Reuchlin, a humanist scholar. Other humanists came to Reuchlin's defense including Ulrich von Hutten who convinced the imperial knight, Franz von Sickingen, to retaliate against Hoogstraaten by beginning a formal feud against the Dominicans. At the same time Rome was becoming convinced that the growing enthusiasm for Luther's teachings were problematic. The Dominicans in Heidelberg were in a confused state; although they were clearly Erasmian, they were not prepared to follow Luther. All this left Bucer feeling extremely isolated. During 1519 he established contacts with other humanists as well as sympathisers of Luther including Wolfgang Capito, George Spalatin, and Ulrich von Hutten. On 11 November 1520 he wrote a letter to Capito in which he revealed that Hoogstraaten was threatening to make an example of him as a follower of Luther. Bucer needed to be freed of his monastic vows in order to escape from the jurisdiction of the Dominicans. Capito and other associates of Bucer were able to expedite the annulment of his monastic vows and on 29 April 1521 he was formally released.
For the next two years, Bucer was associated with Sickingen and Hutten. He also worked for a short period as the court chaplain of Frederick II, Count Palatine of the Rhine, although it is unclear how he obtained this post. This provided the opportunity for Bucer to live in Nuremburg, the most powerful city of the Empire whose governing officials were strongly influenced by the Reformation. Here he met many people who shared his concerns including the humanist, Willibald Pirckheimer, and Andreas Osiander, the future reformer of Nuremburg. In September 1521, Sickingen offered Bucer the position of pastor of the town of Landstuhl. Bucer took his offer and moved to Landstuhl in May 1522. Sometime during the six months that he lived there, he met and married Elisabeth Silbereisen, a former nun. Sickingen also offered to pay for Bucer's studies in Wittenberg. For this, Bucer planned on traveling to Strasbourg to leave his wife with his parents and then travel alone to Wittenberg. While on his way to Strasbourg, he stopped in the town of Wissembourg, where the leading reformer of the town, Heinrich Motherer, asked him to become his chaplain. Bucer agreed and he went to work immediately, preaching daily sermons in which he attacked traditional church practices and monastic orders. He summarised his convictions in six theses and arranged for a public disputation. However, his opponents, the Franciscans and Dominicans of Wissembourg, simply ignored him. His sermons did stir up the people of Wissembourg to the point of threatening the town's monasteries. The bishop of Speyer reacted by excommunicating Bucer. The town council continued to support him, but events occurring outside Wissembourg sealed his fate. Bucer's leading benefactor, Sickingen, was defeated in Trier during the Knight's Revolt and the forces of the Reformation began to retreat. The council urged Bucer and Motherer to leave and on 13 May 1523, they fled to Strasbourg.
It was the largest guild in Strasbourg and also one of the poorest, the Gärtner or Gardeners, that eventually assisted Bucer in his integration into the community. The members of the parish of St Aurelian were mostly from this guild and in January 1524 they made a request to the council for an evangelical preacher to lead their Sunday services. On 20 February, the Gardeners asked Bucer to preach for them. Pleased with his performance, they chose him as their preacher, but the council remained reluctant in appointing him as he was a married and excommunicated priest. On 24 August, the guild used a special assembly under its control in order to push through Bucer's appointment. The council then accepted his application for citizenship on 22 September.
Bucer joined an illustrious team of reformers including Matthew Zell, the preacher of the masses, Wolfgang Capito, the most influential theologian of the city, and Caspar Hedio, the cathedral preacher. He became more active in the reform cause by debating Thomas Murner in which Bucer repudiated the idea that the rite of mass was a true sacrifice. The city council, however, vacillated on the religious issues while the number of people supporting the Reformation continued to rise. Hostility for the clergy grew and emotions reached the boiling point when on 20 August, Conrad Treger, the prior provincial of the Augustinians, attacked not only the reformed preachers but he also labelled all the burghers of Strasbourg as heretics. On 5 September angry mobs formed and broke into the monasteries, looting and destroying religious images. Many opponents of the Reformation were arrested including Treger. The council finally took action and requested an official statement from the evangelical ministers. Bucer drafted twelve articles summarising the teachings of the Reformation including justification by faith and the rejection of the mass and other concepts such as monastic vows, saint veneration, purgatory, and the traditional liturgy. He rejected the authority of the pope and emphasised obedience to the government. Treger was released on 12 October and left Strasbourg. With his departure, overt opposition to the Reformation came to an end.
The reformers' first goal was the creation of a new order of service. They presented their views to the theologians of Wittenberg and Zürich in order to propose a common order of service for the entire Reformation movement. However, the future conflict over the interpretation of the Lord's Supper that would eventually divide the two cities and the two leading reformers, Luther and Zwingli, was already beginning. At this point, the Strasbourg reformers clearly followed the liturgical model of Zwingli. In Bucer's booklet Grund und Ursach (Ground and Cause) published in December 1524, he not only attacked the idea of the mass as a sacrifice, but he also rejected liturgical garments, the altar, and any form of ritual. By May 1525 the reforms were implemented in the parish churches, but the city council decided to retain the holding of mass in the cathedral and the collegiate churches.
From the end of 1524, Bucer concentrated on the major dividing issue within the reformed camp: the understanding of the Eucharist. Bucer played the role of the man of dialogue between Zwingli and Luther.
Bucer, considered to have been one of the most influential and important Protestant theologians of his time, was not always clear regarding his position on conflicting views between Luther and Zwingli. He wrote his main theological work, De Regno Christi in two large volumes for King Edward VI. He did not live to see his larger ten volume treatise on theology, of which only the first volume was published. In the year 1530, he published a summary of his theology Confessio Tetrapolitana.
The confession is noteworthy as it contains his views on the relations of Christ to his mother Mary. Bucer believed that the “Blessed Virgin Mary gave birth to Jesus”, through the Holy Spirit". Bucer encouraged Protestant veneratation of Mary, “because the Mother of God should be honoured most industriously”. This can only happen according to Bucer, “if one does, what she demands, most of all, purity, innocence and piety, for which she gave such wonderful examples”. Bucer believed in the perpetual virginity of Mary, who in his view, lives now in glory with her son in heaven, where she together with the saints prays for us. Bucer asks Protestants not for prayers to Mary, but for praying the Hail Mary in order to honour her. Like Martin Luther, he supports three Marian holidays.
In 1557 Catholic Queen Mary's commissioners exhumed and burnt his body (along with that of Paul Fagius, also considered an heretic) and demolished his tomb; it was subsequently restored by order of Queen Elizabeth I. Bucer is said to have written ninety-six treatises, among them a translation and commentary of the Psalms (one of the first of its kind from the Hebrew text published in 1529), Grund und Ursach (a detailed account of Strassburg reforms to the Roman Mass published in 1524) and De regno Christi (his last major publication; written for Edward VI in 1550). His name is familiar in English literature from the use made of his doctrines by Milton in his divorce treatises.