Thomas grew up and was educated in Villanueva de los Infantes, in the province of Ciudad Real, Spain, where his parents owned a prosperous estate; therefore the name Thomas of Villanueva. Part of the original house still stands, with a coat of arms in the corner, beside a family chapel. In spite of his family's wealth, as a young boy he often went about naked because he had given his clothing to the poor.
Even though he studied Arts and Theology at the University of Alcalá de Henares and became a professor there, he decided to enter the Augustinian order in Salamanca in 1516, and in 1518 was ordained a priest. Within the order, he held the positions of prior of the friary, General Visitor, and Provincial Prior for Andalusia and Castile. He was also a professor at the university and counsellor and confessor to the Spanish King and Holy Roman Emperor Charles V.
He was well known for his great personal austerity (he sold the straw mattress on which he slept in order to give money to the poor) and for his continual and untiring charitable efforts, especially towards orphans, poor women without a dowry, and the sick. He possessed, however, an intelligent notion of charity, so that while he was very charitable, he sought to obtain definitive and structural solutions to the problem of poverty; for example, giving work to the poor, thereby making his charity bear fruit. "Charity is not just giving, rather removing the need of those who receive charity and liberating them from it when possible," he wrote.
In 1533, he sent out the first Augustinian friars to arrive in Mexico. He began to experience mystical ecstasies during Mass and when reading the psalms. Charles V offered him the post of Archbishop of Granada but he would not accept it. In 1544 he was nominated as Archbishop of Valencia but he continued to refuse the position until ordered to accept by his superior. There, aided by his assistant bishop, Juan Segriá, he put in order a diocese that for a century had not had direct pastoral government. He organized a special college for Moorish converts, and in particular an effective plan for social assistance, welfare, and charity.
He composed beautiful sermons, among which stands out the Sermon on the Love of God, one of the great examples of sacred oratory of the 16th century. He enjoyed great fame as a preacher, with a plain and simple style. Charles V, upon hearing him preach, exclaimed, "This monsignor can move even the stones!", and he brought about public conversions. Some of his sermons attacked the cruelty of bullfighting. He also had a great devotion to the Virgin Mary, whose heart he compared to the burning bush that is never consumed. In 1547 he ordained as a priest the future Saint Luis Beltrán. He died in 1555 of angina at the age of 67. He was canonized by Pope Alexander VII on November 1, 1658. His liturgical feast day is celebrated on September 22.
He is the author of various Tracts, among which is included the Soliloquy between God and the soul, on the topic of communion. Francisco de Quevedo wrote his biography. His complete writings were published in six volumes as Opera omnia, in Manila in 1881.
He is the namesake and patron saint of Villanova University, near Philadelphia (USA), which was founded and is administered by the friars of his order, Universidad Católica de Santo Tomás de Villanueva in Havana (Cuba), St. Thomas University in Miami Gardens, Florida, (USA)and Villanova College, a catholic school for boys located in Brisbane, Australia.