He then wandered as a preacher through Italy and Turkey and achieved a great reputation, and suggested that the Messianic kingdom would come in 1535 or 1540. Returning to Italy, he was opposed by prominent Jews including Jacob Mantino ben Samuel, who feared that he might cause unrest among the Jews.
He was given an audience before Pope Clement VII and gained his favor, as well as that of some Judeophile cardinals at Rome. He warned the Pope to leave Rome as the city would soon be flooded and he sent a message to the king of Portugal warning of an imminent earthquake. The occurrence of a deadly flood on October 8, 1530, and an earthquake in Lisbon on January 26, 1531, raised Rabbi Molcho’s reputation among the religious and political authorities.
In company with David Reubeni, his mentor, he went in 1532 to Ratisbon, where the emperor Charles V was holding a diet. On this occasion, Rabbi Molcho carried a flag with the Hebrew word Maccabi, the four letters which also signify an abbreviation for Exodus 15:11 "Who among the mighty is like unto God?". The three met for two hours, and while the exact content of the meeting was not recorded, letters written from the court at the time indicate Molcho proposed the establishment of a joint Jewish-Christian army to fend off the emperor’s foreign enemies and, possibly, to reconquer the Holy Land. The emperor had both Rabbi Molcho and Reubeni arrested and took them back to Italy. In Mantua an ecclesiastical court sentenced Rabbi Molcho to death by fire. Rabbi Molcho was taken to the stake in November or December 1532 (a Jewish tradition lists the date as 5th of Tevet 5293 but there are no records to confirm the date). It is claimed the emperor offered to pardon him on condition that he return to the Catholic Church, but Rabbi Molcho refused, asking for a martyr's death. His mentor, David Reubeni, was exiled to Spain, where later he died.