Lawrence Calcagno was born on March 23, 1913, in Potrero Hill, San Francisco, California. His parents, Vincent and Anna de Rosa Calcagno were Italian immigrants. At age ten he moved to the family ranch-homestead in the Santa Lucia Mountains, Monterey County where he spent the following ten years.[3] In 1935 he left the homestead and joined the merchant marines and traveled all the way to Asia.

In 1941 at the beginning of World War II Calcagno joined the United States Army Air Corps, where he served for three years. During his service he was recognized as an artist. His drawing titled: "Watch in the Night" won first prize in the national Army art contest in the Southwest Regional competition.

Benefiting from the G.I. Bill in 1947 Lawrence Calcagno enrolled at the California School of Fine Arts, San Francisco, California. His teachers were Mark Rothko, Clyfford Still & Ad Reinhardt along with instructors, Edward Corbett and Richard Diebenkorn. In 1950 he left California School of Fine Arts for Europe. He went to Paris, France to study at L’Academie de la Grande Chaumiere. In 1951 he went to Florence to study the Renaissance. He enrolled at the Instituto d’Arte Statale.

Beauford Delaney and Lawrence Calcagno and unlikely pair, the two became friends in Paris in the early 1950s and remained close over the next twenty years.

But Delaney and Calcagno had many things in common. Both men committed themselves wholeheartedly to lyrical abstraction, though Delaney's work was ultimately influenced more by Claude Monet's fluid water-lily paintings than by the color-field painters so important in Calcagno's formation as an artist. Both men shared an interest in the philosophical underpinnings of their abstract work. Calcagno's abstract "landscapes of the mind"—with their recognizable and consistent horizons—derived in part from the artist's sense of the universal, yet mysterious harmony of nature. Through Delaney, Calcagno also became friends with James Baldwin and the three travelled together.

The relationship between Beauford and Larry Calcagno can be summarized in a single phrase that Beauford wrote in a letter to Calcagno in 1968, in which he described a “deathless kinship that is constant [and] is always alive and close between us.”

He continued to work and study in Paris until 1955. During this time, Calcagno became acquainted with Martha Jackson, who mounted his first one-man at her New York gallery in 1955.

He developed a gift for teaching as well as painting, working at New York University and eventually Carnegie Mellon University.

In 1956 Calcagno accepted the position of assistant professor in the art department at the Albright Art School in the University at Buffalo, New York where he stayed until 1958. He went on to teach from 1958 to 1959 at the University of Illinois, Urbana. In 1960 he moved to New York and became a part-time instructor at New York University.

Calcagno was friends with the African American artist Jack Whitten. In 1964 Calcagno supported Whitten alongside artists Romare Bearden, Jacob Lawrence and Wayne Thiebaud to secure Whitten a grant for minority artists from the John Hay Whitney Fellowship.

In 1965 Calcagno became Andrew Mellon Professor in Painting at Carnegie Mellon University, in Pittsburgh, Pennsylvania, where he stayed until 1968. Calcagno was a fellow at the McDowell and Yaddo artist colonies in 1960s.