Self-titled "the most Colombian of Colombian artists" early on, he came to national prominence when he won the first prize at the Salón de Artistas Colombianos in 1958. Working most of the year in Paris, in the last three decades he has achieved international recognition for his paintings, drawings and sculpture, with exhibitions across the world. His art is collected by many major international museums, corporations, and private collectors. In 2012, he received the International Sculpture Center's Lifetime Achievement in Contemporary Sculpture Award.
Fernando Botero was born the second of three sons to David Botero (1895–1936) and Flora Angulo (1898–1972). David Botero, a salesman who traveled by horseback, died of a heart attack when Fernando was four. His mother worked as a seamstress. An uncle took a major role in his life. Although isolated from art as presented in museums and other cultural institutes, Botero was influenced by the Baroque style of the colonial churches and the city life of Medellín while growing up.
He received his primary education in Antioquia Ateneo and, thanks to a scholarship, he continued his secondary education at the Jesuit School of Bolívar. In 1944, Botero's uncle sent him to a school for matadors for two years. In 1948, Botero at age 16 had his first illustrations published in the Sunday supplement of the El Colombiano, one of the most important newspapers in Medellín. He used the money he was paid to attend high school at the Liceo de Marinilla de Antioquia.
Botero's work was first exhibited in 1948, in a group show along with other artists from the region.
From 1949 to 1950, Botero worked as a set designer, before moving to Bogotá in 1951. His first one-man show was held at the Galería Leo Matiz in Bogotá, a few months after his arrival. In 1952, Botero travelled with a group of artists to Barcelona, where he stayed briefly before moving on to Madrid.
In Madrid, Botero studied at the Academia de San Fernando. In 1952, he traveled to Bogotá, where he had a solo exhibit at the Leo Matiz gallery.
In 1953, Botero moved to Paris, where he spent most of his time in the Louvre, studying the works there. He lived in Florence, Italy from 1953 to 1954, studying the works of Renaissance masters. In recent decades, he has lived most of the time in Paris, but spends one month a year in his native city of Medellín. He has had more than 50 exhibits in major cities worldwide, and his work commands selling prices in the millions of dollars. In 1958, he won the ninth edition of the Salón de Artistas Colombianos.
While his work includes still-lifes and landscapes, Botero has concentrated on situational portraiture. His paintings and sculptures are united by their proportionally exaggerated, or "fat" figures, as he once referred to them.
Botero explains his use of these "large people", as they are often called by critics, in the following way:
"An artist is attracted to certain kinds of form without knowing why. You adopt a position intuitively; only later do you attempt to rationalize or even justify it."
Botero is an abstract artist in the most fundamental sense, choosing colors, shapes, and proportions based on intuitive aesthetic thinking. Though he spends only one month a year in Colombia, he considers himself the "most Colombian artist living" due to his isolation from the international trends of the art world.
In 2004, Botero exhibited a series of 27 drawings and 23 paintings dealing with the violence in Colombia from the drug cartels. He donated the works to the National Museum of Colombia, where they were first exhibited.
In 2005, Botero gained considerable attention for his Abu Ghraib series, which was exhibited first in Europe. He based the works on reports of United States forces' abuses of prisoners at Abu Ghraib prison during the Iraq War. Beginning with an idea he had on a plane journey, Botero produced more than 85 paintings and 100 drawings in exploring this concept and "painting out the poison". The series was exhibited at two United States locations in 2007, including Washington, DC. Botero said he would not sell any of the works, but would donate them to museums.
In 2006, after having focused exclusively on the Abu Ghraib series for over 14 months, Botero returned to the themes of his early life such as the family and maternity. In his Une Famille Botero represented the Colombian family, a subject often painted in the seventies and eighties. In his Maternity, Botero repeated a composition he already painted in 2003, being able to evoke a sensuous velvety texture that lends it a special appeal and testifies for a personal involvement of the artist. The child in the 2006 drawing has a wound in his right chest as if the Author wanted to identify him with Jesus Christ, thus giving it a religious meaning that was absent in the 2003 artwork.
In 2008, he exhibited the works of his The Circus collection, featuring 20 works in oil and watercolor. In a 2010 interview, Botero said that he was ready for other subjects: "After all this, I always return to the simplest things: still lifes."
Between 1963 and 1964, Fernando Botero attempted to create sculptures. Due to financial constraints preventing him from working with bronze, he made his sculptures with acrylic resin and sawdust. A notable example during this time was "Small Head (Bishop)" in 1964, a sculpture painted with great realism. However, the material was too porous and Botero decided to abandon this method.
Botero has donated several artworks to museums in Bogotá and his hometown, Medellín. In 2000, Botero donated to the Museo Botero in Bogotá 123 pieces of his work and 85 pieces from his personal collection, including works by Chagall, Picasso, Robert Rauschenberg, and the French impressionists. He donated 119 pieces to the Museum of Antioquia. His donation of 23 bronze sculptures for the front of the museum became known as the Botero Plaza. Four more sculptures can be found in Medellín's Berrio Park and San Antonio Plaza nearby.
Botero married Gloria Zea (who became the Colombian Minister of Culture). Together they had three children: Fernando, Lina, and Juan Carlos. The senior Boteros divorced in 1960 and each remarried. Starting in 1960, Botero lived for 14 years in New York, but more recently has settled in Paris. Lina also lives outside of Colombia, and in 2000 Juan Carlos moved to southern Florida.
In 1964, Botero began living with Cecilia Zambrano. They had a son, Pedro, born in 1974, who was killed in 1979 in a car accident in which Botero was also injured. Botero and Zambrano separated in 1975.
Last Botero married the Greek artist Sophia Vari. They reside in Paris and have a house in Pietrasanta, Italy. Botero's 80th birthday was commemorated with an exhibition of his works at Pietrasanta."Fund-Raiser" Exhibition with Sonia Falcone at Calvin Charles Gallery  (2003), Scottsdale, Arizona.
"Botero at Ebisu" (2004), Tokyo
"Fernando Botero" (2006), Athens
"The Baroque World of Fernando Botero" (2007), Quebec City
"Abu Ghraib Exhibit" (2007), University of California, Berkeley
"Botero: Abu Ghraib" (November 6 - December 30, 2007), American University Museum
"Botero Abu Ghraib" Exposition (2008), Centro de las Artes I Monterrey, Mexico
"The Baroque World of Fernando Botero" (May 2008), Delaware Art Museum, Wilmington
"The Baroque World of Fernando Botero" (June 28 - September 21, 2008), New Orleans Museum of Art
"The Baroque World of Fernando Botero" (May 30 - August 16, 2009), Colorado Springs Fine Arts Center
"The Baroque World of Fernando Botero" (October 19 - January 11, 2009), Brooks Museum of Art, Memphis, Tennessee
"The Baroque World of Fernando Botero" (September 12, 2009 - December 6, 2009), Bowers Museum, Santa Ana, California
"Fernando Botero" (September 2009) Korea, Seoul, Bandi Gallery
"Fernando Botero: Works On Paper, Paintings, and Sculptures" (February 11 - March 28, 2010), David Benrimon Fine Art, New York, NY
"The Baroque World of Fernando Botero" (May 1 - July 25, 2010), Nevada Museum of Art, Reno, Nevada
"Botero" (4 May - 18 July 2010), Pera Museum, Istanbul 
"The Baroque World of Fernando Botero" (August 21 - November 14, 2010), Glenbow Museum, Calgary
"The Baroque World of Fernando Botero" (December 10, 2010 - February 27, 2011), Winnipeg Art Gallery, Winnipeg
"Botero" (October 2011 - January 2012), Kunstforum, Vienna
"Fernando Botero" (July 2015 - October 2015), Seoul Arts Center, Seoul
"Botero in China" (November 2015 - January 2016), The National Museum of China, Beijing
"Botero in China" (January 2016 - April 2016), China Art Museum, Shanghai
"Botero: Celebrate Life!" (July 2016 - September 2016), Kunsthal Rotterdam, Netherlands