Joaquín was born in Paco, Manila, one of the ten children of Leocadio, a colonel under General Emilio Aguinaldo in the 1896 Revolution, and Salome Marquez, a teacher of English and Spanish. Being read poems and stories by his mother, Joaquin taught himself by reading widely at the National Library of the Philippines and the library of his father, who by that time was a successful lawyer after the revolution. This developed further his interest in writing.

At age 17, Joaquín was first published in the literary section of the Pre-World War II Tribune under writer and editor Serafín Lanot. Before publishing in the Tribune, Joaquin worked as a proofreader of the paper.

After winning a Dominican Order-sponsored nationwide essay competition for La Naval de Manila, the University of Santo Tomas awarded Joaquín an honorary Associate in Arts (A.A.) and a scholarship to St. Albert's Convent, the Dominican monastery in Hong Kong. Upon his return to the Philippines, he joined the Philippines Free Press, starting as a proofreader. Soon, he was noticed for his poems, stories and plays, as well as his journalism under the pen name Quijano de Manila. His journalism was markedly both intellectual and provocative, an unknown genre in the Philippines at that time, raising the level of reportage in the country.

Joaquín deeply admired José Rizal, the national hero of the Philippines. Joaquín paid tribute to Rizal by way of books such as The Storyteller's New Medium - Rizal in Saga, The Complete Poems and Plays of Jose Rizal, and A Question of Heroes: Essays in Criticism on Ten Key Figures of Philippine History. He also translated the hero's valedictory poem, in the original Spanish "Mi Ultimo Adios," as "Land That I Love, Farewell!"

Joaquín served as a member of Motion Pictures under President Diosdado Macapagal and President Ferdinand E. Marcos. Joaquin's first move as National Artist was to secure the release of imprisoned writer José F. Lacaba. Later, at a ceremony on Mount Makiling attended by First Lady Imelda Marcos, Joaquín delivered an invocation to Mariang Makiling, the mountain's mythical maiden. Joaquín touched on the importance of freedom and the artist. As a result, for the remainder of the Marcos regime, Joaquín no longer received invitations to address important cultural events.

Joaquín died of cardiac arrest in the early morning of April 29, 2004. He died in his home in San Juan, Metro Manila. At the time of his death, he was editor of Philippine Graphic magazine and publisher of its sister publication, Mirror Weekly, a women’s magazine. He also wrote columns (“Small Beer”) for the Philippine Daily Inquirer and Isyu, an opinion tabloid.

Tatarin, a movie based on Philippine National Artist Nick Joaqin’s short story The Summer Solstice, was directed by Amable “Tikoy” Aguiluz and released in 2001. The screenplay was written by Ricardo Lee. Nick Joaquin was consulted on his portrayal. The cast consisted of famous Filipino actors Edu Manzano (Paeng Moreta,) Dina Bonnevie (Lupe Moreta), Rica Peralejo (Amada), and Raymond B. Bagatsing.