Botero's first known works are drawings: the illustrations for the literary supplement of the El Colombiano newspaper in Medellín. In 1951, after moving to Bogotá, he had his first individual exhibition at the Leo Matiz gallery, presenting watercolors, gouaches, ink drawings, and oils. With the sales of some of his works exhibited on that occasion, he settled in Tolú. On his return to the capital, he exhibited again, this time with more success. At the IX National Artists’ Salon, held in 1952, Botero won second prize in oil painting with “Frente al mar” (In Front of the Sea). He was 20 years old at the time and decided to travel to Europe. He spent a short time at the San Fernando Academy in Madrid and then at the San Marco Academy in Florence, where he took classes on the art of the Italian Quattrocento with Roberto Longhi.

He remained in Europe until 1955. Of these years in Europe, Botero has commented: "I actually consider myself self-taught. I worked for three years in fine arts schools, but practically never had a teacher. I learned by reading, going at museums, and above all painting."

In 1956 he traveled to Mexico, then to Washington and New York. On his return to Colombia in 1957, his oil painting Contrapunto he shared the second prize in painting at the X National Artists’ Salon with Alejandro Obregón and Jorge Elías Triana. In 1958, he won the first prize in the XI National Artists’ Salon, with the oil painting La camera degli sposi (Homage to Mantegna). Since then, Botero's dealings with the great masters of the past and with a few modern ones have been constant. Botero strove to—and indeed did—paint and draw like the best. In pursuit of this aim he not only visited the museums and methodically studied techniques and procedures but also worked long hours. This familiarity with and admiration for art since the Renaissance explains the charcoal work Dinner with Ingres and Piero della Francesca (1972), in which Botero sits at the table with the French Neoclassical painter and the great Italian painter of the Quattrocento.

But although Botero has taken a seat at the table with European masters thanks to his talent, commitment, and hard work, Botero continues to be an artist from Latin America, from Colombia, and even from Medellin: "Many artists believe that art becomes universal if you copy universally. I don't think so. I think you have to be honest with yourself, and by being honest you can reach people all over the world [...] I am the most Colombian of Colombian artists, even though I have lived outside of Colombia for so long, since 1960 [...] In a way, I paint Colombia the way I want it to be, but it is not really like that. It is an imaginary Colombia that both is and is not the same as the true Colombia.” In 1961, he moved to New York, where he worked for twelve years. He then settled in Paris. Nevertheless, Botero is a true representative of Latin American art not only because of his themes of nuns, prelates, military men, brothels, villages with simple houses, and still lifes with tropical fruits, but also because of his magical realism.

Botero stated in 1967: "I am a protest against modern painting and yet I use what is hidden behind its back, playing ironically with everything that is absolutely known to everyone. I paint figuratively and realistically, but not in the flat sense of fidelity to nature. I never give a brushstroke that does not describe something real: a mouth, a hill, a pitcher, a tree. But what I describe is a reality found by me. It could be formulated in this way: I describe realistically an unrealistic reality.” Tracy Atkinson, one of several foreign critics who have discussed Botero’s work, wrote, "Botero’s world is people in a broad sense. A repertoire that is generally absurd and a bit pathetic. But the warmth and sympathy of its treatment saves it from its ugliness and makes it instantly unforgettable. The artist’s attitude is so intense and consistent that it reaches into all things”.

In Botero’s paintings are figures encircled by lines. Even in his Expressionist phase, we see vehement strokes that define the representation. His oeuvre contains large format drawings, many on canvas. Undoubtedly, Botero gives special importance to drawing.