In 1261 Thomas was nominated conventual lector at Orvieto where he began a period of intense activity. He finished the writing of the Summa contra gentiles. He made many trips as a Preacher General of the Order of Preachers. He was occupied with the formation of the Brothers, taking up with them the teaching of dogmatics on a regular schedule; however, he did this for a pastoral end and thereby rectified in a noteworthy way the traditional teaching. As a Master he commented on the Scriptures, in particular the book of Job (Expositio super Iob ad litteram).

His literary activities were numerous. He wrote different small pieces in answer to requests made to him by Popes, bishops, disciples, and friends. There was De emptione et venditione sulla speculazione finanziaria, a subject which entered Thomas's thought in relation to problems of his time. The Errores contra Graecorum, written at the request of Pope Urban IV, is in reality an examination of a sketchy and grandiloquent florilegium of greek, patristic texts that are examined critically. The De rationibus fidei ad Cantorem Antiochenum gives valuable, methodological directions on how to use arguments from reason to defend Christian truth against non-believers and arguments of faith against heretical christians. There is the Expositio super primam et secundam decretalem of the fourth Lateran Council, with the "Credo firmiter" and the dogmatic text rejecting the errors of Joachim of Fiore. The De articulis fidei et Ecclesiae, a doctrinal synthesis on the faith and the sacraments, takes into account the more frequently occurring errors. The Super librum Dionysii De Divinis nominibus goes back to his days in Cologne where Thomas was familiar with and wanted to study more profoundly the De Divinis nominibus, granted its presumed apostolic authority. The neo-Platonic character of this work together with exacting analogies of the history of salvation fit nicely into Thomas's thinking.

Also at Orvieto Thomas composed two liturgical texts. One was the hymn Adoro te. The other, written at the command of Pope Urban IV, was the Officium de festo Corporis Christi whose authenticity is even now not certain, although it is well situated in the spiritual development of Thomas's christology which extended to the eschatological and experimental vision of the glorified Christ, starting from the hidden, but real, experience of Him that the Eucharist offers to us.

The important Glossa continua super Evangelia, widely known as the Catena aurea, written at the request of Pope Urban IV, was begun in this period but was to be finished a little later. It has the form of a commentary proceding verse by verse through the four Gospels, but it is made up of many exegetical citations from the Fathers of the Church. Of these Thomas, for a person of this time, appears to have had an exceptional knowledge. He fully considered that they were a font of theology. Thomas made us of earlier personal collections. The work was written out with the help of secretaries and others who translated texts from the Greek.