Born in Medellin, Colombia, Botero moved to Bogota in 1951 and had his first international show at the Leo Matiz Gal. Leaving for Madrid in 1952, he studied at the San Fernando Academy and, from 1953 until 1955, studied fresco technique and art history in Florence which has influenced his painting ever since. Returning to Colombia, he exhibited at the Biblioteca Nacional in Bogota and began teaching at the School of Fine Arts of the National University; the same year, he spent time in Mexico studying the political murals of Rivera and Orozco, whose influence is evident in his political perspective.

Botero's visit to the United States in the late 1950s prompted a return to live and work in New York for ten years beginning in 1960. Although Abstract Expressionism interested him, he sought his primary inspiration from the Italian Renaissance. During this period he began to experiment with creating volume in his paintings by expanding the figures and compressing the space around them, a quality which he continues to explore whether painting imaginary group portraits or parodies on the work of famous masters.

Widely exhibited in Europe and North and South America, Botero has received numerous awards including the First Intercol at the Museum of Modern Art in Bogota, and is included in major museums worldwide. Since the early 1970s, Botero has divided his time between Paris, Madrid and Medellin.