He was born in Marianella, near Naples, then part of the Kingdom of Naples, on 27 September 1696. He was the eldest of eight children of Giuseppe and Anna Cavalieri Liguori. Two days after he was born, he was baptized at the Church of Our Lady the Virgin as Alphonsus Mary Anthony John Cosmas Damian Michael Gaspard de' Liguori. The family was of noble and ancient lineage, but the branch to which the Saint belonged had become somewhat impoverished. Alphonsus's father, Don Joseph de' Liguori, was a naval officer and Captain of the Royal Galleys. His mother was of Spanish descent.

In 1723, he decided to offer himself as a novice to the Oratory of St. Philip Neri with the intention of becoming a priest. His father opposed the plan, but after two months (and with his Oratorian confessor's permission), he and his father compromised: he would study for the priesthood but not as an Oratorian and live at home. He was ordained on 21 December 1726, at 30. He lived his first years as a priest with the homeless and the marginalized youth of Naples. He became very popular because of his plain and simple preaching. He said: "I have never preached a sermon which the poorest old woman in the congregation could not understand". He founded the Evening Chapels, which were managed by the young people themselves. The chapels were centers of prayer and piety, preaching, community, social activities and education. At the time of his death, there were 72, with over 10,000 active participants. His sermons were very effective at converting those who had been alienated from their faith.

In 1729, Alphonsus left his family home and took up residence in the Chinese Institute in Naples. It was there that he began his missionary experience in the interior regions of the Kingdom of Naples, where he found people who were much poorer and more abandoned than any of the street children in Naples. In 1731, while he was ministering to earthquake victims in the town of Foggia, Alphonsus claimed to have had a vision of the Virgin Mother in the appearance of a young girl of 13 or 14, wearing a white veil.

A gifted musician and Composer, he wrote many popular hymns and taught them to the people in parish missions. In 1732, while he was staying at the Convent of the Consolation, one of his order's houses in the small city of Deliceto in the province of Foggia in Southeastern Italy, Liguori wrote the Italian carol "Tu scendi dalle stelle" ("From Starry Skies Descending") in the musical style of a pastorale. The version with Italian lyrics was based on his original song written in Neapolitan, which began Quanno nascette Ninno (When the child was born). As it was traditionally associated with the zampogna, or large-format Italian bagpipe, it became known as Canzone d'i zampognari the ("Carol of the Bagpipers").

Alphonsus' greatest contribution to the Church was in the area of moral theology. His masterpiece was The Moral Theology (1748), which was approved by the Pope himself and was born of Alphonsus' pastoral experience, his ability to respond to the practical questions posed by the faithful and his contact with their everyday problems. He opposed sterile legalism and strict rigorism. According to him, those were paths closed to the Gospel because "such rigor has never been taught nor practiced by the Church". His system of moral theology is noted for its prudence, avoiding both laxism and excessive rigor. He is credited with the position of Aequiprobabilism, which avoided Jansenist rigorism as well as laxism and simple probabilism. Since its publication it has remained in Latin, often in 10 volumes or in the combined 4-volume version of Gaudé. It saw only recently its first publication in translation, in an English translation made by Ryan Grant and published in 2017 by Mediatrix Press. The English translation of the work is projected to be around 5 volumes.

Alphonsus was consecrated Bishop of Sant'Agata dei Goti in 1762. He tried to refuse the appointment by using his age and infirmities as arguments against his consecration. He wrote sermons, books, and articles to encourage devotion to the Blessed Sacrament and the Blessed Virgin Mary. He first addressed ecclesiastical abuses in the diocese, reformed the seminary and spiritually rehabilitated the clergy and faithful. He suspended those Priests who celebrated Mass in less than 15 minutes and sold his carriage and episcopal ring to give the money to the poor. In the last years of his life, he suffered a painful sickness and a bitter persecution from his fellow Priests, who dismissed him from the Congregation that he had founded.

In 1775, he was allowed to retire from his office and went to live in the Redemptorist community in Pagani, Italy, where he died on 1 August 1787.

He was beatified on 15 September 1816 by Pope Pius VII and canonized on 26 May 1839 by Pope Gregory XVI.

He was canonized in 1839 by Pope Gregory XVI and proclaimed a Doctor of the Church by Pope Pius IX in 1871. One of the most widely read Catholic authors, he is the patron saint of confessors.

In 1949, the Redemptorists founded the Alphonsian Academy for the advanced study of Catholic moral theology. He was named the patron of confessors and moral Theologians by Pope Pius XII on 26 April 1950, who subsequently wrote of him in the encyclical Haurietis aquas.

His Mariology, though mainly pastoral in nature, rediscovered, integrated and defended that of St Augustine of Hippo, St Ambrose of Milan and other fathers; it represented an intellectual defence of Mariology in the 18th century, the Age of Enlightenment, against the rationalism to which his often flaming Marian enthusiasm contrasted.