He was born at Ebernburg (now Bad Münster am Stein-Ebernburg) near Bad Kreuznach. Having fought for the emperor Maximilian I against Venice in 1508, he inherited large estates on the Rhine, and increased his wealth and reputation by devious methods. In 1513 he took up the quarrel of Balthasar Schlör, a citizen who had been driven out of Worms, and attacked this city with 7000 men. In spite of the imperial ban, he devastated its lands, intercepted its commerce, and desisted only when his demands were granted. He made war on Antoine, Duke of Lorraine, and compelled Philip, Landgrave of Hesse, to pay him 35,000 gulden. In 1518 he interfered in a civil conflict in Metz, ostensibly siding with the citizens against the governing oligarchy. He led an army of 20,000 against the city, compelled the magistrates to give him 20,000 gold gulden and a month's pay for his troops. In 1518 Maximilian released him from the ban, and he took part in the war carried on by the Swabian League against Ulrich, Duke of Württemberg.
In the contest for the imperial throne upon the death of Maximilian in 1519, Sickingen accepted bribes from King Francis I of France, but when the election took place he led his troops to Frankfurt, where their presence assisted to secure the election of Charles V, Holy Roman Emperor. For this service he was made imperial chamberlain and councillor, and in 1521 he led an expedition into France, which ravaged Picardy, but was beaten back from Mezières and forced to retreat.
In about 1517 Sickingen became intimate with Ulrich von Hutten, and gave his support to Hutten's schemes. In 1519 a threat from him freed Johann Reuchlin from his enemies, the Dominicans, and his castles became (in Hutten's words) a refuge for righteousness. Here many of the reformers found shelter, and a retreat was offered to Martin Luther.
After the failure of the French expedition, Sickingen, aided by Hutten, formed, or revived, a large scheme to overthrow the spiritual princes and to elevate the order of knighthood, the Knights' Revolt. He hoped to secure this by the help of the towns and peasantry. A large army was soon collected, many nobles from the upper Rhineland joined the standard, and at Landau, in August 1522, Sickingen was formally named commander. He declared war against his old enemy, Richard Greiffenklau of Vollraths, archbishop of Trier, and marched against that city. Trier was loyal to the archbishop, and the landgrave of Hesse and Louis V, count palatine of the Rhine, hastened to his assistance. Sickingen, without the help he needed, was compelled to fall back on his castle, Burg Nanstein at Landstuhl, collecting much booty on the way.
On October 22 1522 the council of regency placed him under the ban, to which he replied, in the spring of 1523, by plundering Kaiserslautern. The Archbishop Richard of Trier, Landgrave Philip I of Hesse, and Elector Palatine Louis V decided to move against him, and having obtained help from the Swabian League, marched on Burg Nanstein. Sickingen refused to negotiate, and during the siege was seriously wounded. This attack was one of the first occasions on which artillery was used, and breaches were soon made in an otherwise impregnable fortress. On May 6 1523 Sickingen was forced to capitulate, and on the following day he died. He was buried at Landstuhl, and in 1889 a splendid monument was raised at Ebernburg to his memory and to that of Hutten.
His son Franz Conrad was made a baron of the empire (Reichsfreiherr) by Maximilian II, and a descendant was raised in 1773 to the rank of realm count (Reichsgraf). The last surving branch of the family resides in Austria.