In 1555, he opened his own printing establishment. The first known book he is known to have printed was La Institutione di una fanciulla nata nobilmente, by J. M. Bruto, with a French translation. This was soon followed by many other works in French and Latin, which in point of execution rivalled the best printing of his time. The masters in the art of engraving, then flourishing in the Netherlands, illustrated many of his editions. A bad wound in the arm seems to have led him (about 1555) to apply himself to typography.
In 1562, while Plantin was absent in Paris, his workmen printed a heretical pamphlet, which resulted in his goods being seized and sold. It seems, however, that he eventually recovered much of the value that was taken from him. In 1563, he associated himself with some friends to carry on his business on a larger scale. Among these friends were two grand-nephews of Daniel Bomberg, who furnished him with the fine Hebrew typefaces of that renowned Venetian printer.
In November 1576, Antwerp was plundered and in part burnt by the Spaniards, and Plantin had to pay an exorbitant ransom. He established a branch of his office in Paris. When in 1583 the states of Holland sought a typographer for the newly erected university at Leiden in the Netherlands, he moved there after leaving his much reduced business in Antwerp to his sons-in-law John Moerentorf (Jan Moretus) and Francis van Ravelinghen (Raphelengius). After Antwerp became more settled subsequent to its conquest by the prince of Parma in 1585, Plantin left his Leiden office to Raphelengius and returned to Antwerp, where he laboured until his death on 1 July, 1589.
His editions of the Bible in Hebrew, Latin and Dutch, his Corpus juris, Latin and Greek classics, and many other works produced at this period are renowned for their beautiful execution and accuracy. A much greater enterprise was planned by him in those years—the publication of a Biblia polyglotta, which would fix the original text of Old and New Testaments on a scientific basis. In spite of clerical opposition he was supported by King Philip II of Spain, who sent him the learned Benito Arias Montano to lead the editorship. With Montano's zealous help, the work was finished in five years (1569-1573, 8 vols, folio). This work earned Plantin little profit, but resulted in Philip's granting him the privilege of printing all Roman Catholic liturgical books (missals, breviaries, etc.) for the states ruled by Philip, and the office of prototypo-graphus regius.
Besides the polyglot Bible, Plantin published many other works of note, such as editions of St. Augustine and St. Jerome, the botanical works of Dodonaeus, Clusius and Lobelius, and the description of the Netherlands by Guicciardini. In 1575, his printing office reckoned more than 20 presses and 73 workmen, besides a similar number that worked for the office at home.
Though outwardly a faithful son of the church, he was a lifelong supporter of a mystical sect of heretics. It is now proved that many of their books published without the name of a printer came from his presses.