In 1272, after four years residence in Paris, Thomas returned to Naples with an assignment from his Order to start a general studium in theology, that is to say to reorganize the Faculty of Theology at the University Naples. In Naples Thomas lectured on different subjects. There was a general course on the Epistles of Paul. Only the commentary on Romans 1-8 in the Lectura super Epistolas Pauli Apostoli are certainly written by Thomas. The rest of the text was not revised by him. There was a course on the Psalms, the Postilla super Psalmos. He continued to work on the Tertia pars of the Summa and to answer different theological questions and to respond to requests for works which the mails brought to him. He also preached, probably on the "Our Father", in the vernacular, and had as well the duty to settle some matters dealing with his family's inheritance.

During his last stay in Naples, he had a strong mystical experience that historically almost certainly occurred in the Major Basilica of St. Dominic, when the Crucifix spoke to him saying: "How well you have written of me, Thomas!" Very similar to this experience was the one that occurred in the Autumn of 1273 when the accounts of several witnesses agree that Thomas had an extraordinary change during the celebration of the Eucharist which moved him to the firm decision not to dictate anything any more to his secretaries. When the loyal Reginald objected, Thomas said: "I cannot do it any more. All that I have written seems like straw to me compared to what I have seen." From that moment on Thomas entered into a state of exhaustion which confined him to bed. He urged his superiors to send him to his sister's nearby in the castle of Sanseverino (near Salerno) with the hope he would recover. He remained alone for some time, up until the beginning of 1274.

Then Pope Gregory X wanted him to be present at the soon-to-be-convoked Council of Lyons for the union of Latin with the Eastern Church. At the beginning of the tiring journey, near Teano, Thomas absorbed and distracted violently his head against the branches of a fallen tree. Further on and several days later they stopped at his niece's, Francesca of Maenza, in the vicinity of today's city of Latina. There he got worse, refusing to eat any food. Having been told by the doctor who was taking care of him to eat, he expressed an innocent desire to eat some herring or some fresh anchovies. He barely tasted them. Taking up the journey again, he was obliged to stop at the Cistercian Abbey of Fossanova, where he lay sick for about a month, surrounded by the kindnesses of the monks. He received Viaticum on the first of March and made a moving, public profession of faith in the Eucharist. Father Reginald heard his last Confession, and, having received the anointing of the sick, he died at the first hour of the morning on March the seventh 1274, barely fifty years of age.

If we are to make a judgment on this story, his unforeseen death was probably connected with the spiritual/psychic experience, certainly traumatic having seen his decision to stop writing, which occurred at San Domenico Maggiore. This was a short time before the incident on the journey that perhaps caused a cerebral hemorrhage. One cannot believe in the hypothesis, because it is only legendary, that Thomas was poisoned, perhaps at the order of Charles of Anjou. What is more, both the Cronica of Giovanni Villani and Dante's Comedia knew about this rumor, but contemporary histories agree in rejecting it because it lacks any historical foundation. Instead, it seems to be closer to the truth that the great physical and intellectual energy that Thomas expended without reserve until the last days in teaching, in writing his works, in the innumerable difficult assignments, and in his promises to preach, all these produced in him a general weariness which, united with the mystical experience, brought about the destruction of his strength.

The funeral Mass was solemnly celebrated in the Abbey Church and his body was entombed in the Cloister of the same place. In 1369 the body was sent to Toulouse where it remained until the French Revolution when it was transferred elsewhere for security purposes. It was returned there definitively in 1974, the seven hundredth anniversary of his death.