Van Looy rose to prominence when he won the Belgian amateur road championship in 1952. He repeated the victory the following year, adding third place in the world title race the same year, before turning professional. At the 1952 Summer Olympics, he won a gold medal in the team road race event.
A powerful sprinter, Van Looy won two races in what was left of his first professional season (1953), and 20 more over the next couple of seasons. In 1956, his victories included Gent–Wevelgem and Paris–Brussels, plus two stages and overall victory in the Tour of the Netherlands. He also won a silver medal in the world road race championship, behind his countryman Rik Van Steenbergen. He repeated his Gent–Wevelgem and Tour of the Netherlands victories in 1957, and in 1958 won the season's opening classic, Milan – San Remo.
1959 saw Van Looy take the early-season Tour of Flanders and the autumn classic, the Giro di Lombardia. In between, he scored another 38 victories, including three stages of the Vuelta a España (finishing third overall and winner of the points competition) and four stages of the Giro d'Italia (for 4th overall).
In 1960, he scored the first of two consecutive victories in the world road race championship, but Classic victories eluded him. However, he made up for this in 1961, winning both Paris–Roubaix and Liège–Bastogne–Liège – making him the first rider to take all five 'Monuments' – as well as retaining his rainbow world title jersey, and taking three stages, plus the mountains competition, in the Giro.
Van Looy scored two more Classic wins in 1962 (Paris–Roubaix, Tour of Flanders), took another Gent–Wevelgem, and two more Giro stages. In 1963 Van Looy rode the Tour de France, taking four stages en route to victory in the points competition and a 10th place on general classification; he also grabbed a silver in the world title race. In the latter race, held in Ronse in his native Belgium, he was beaten in the sprint by his countryman Benoni Beheyt. Van Looy, starting the sprint too early, did not take this defeat lightly. This race has remained memorable in the history of Belgian cycling.
In 1965, he scored 42 victories including Paris–Roubaix, and eight stages of the Vuelta on his way to his second third place overall (his highest placing in a Grand Tour). For good measure, he also took two stages in the Tour de France.
During the final years of his career (1966–1970), Van Looy's road performances began to fade, as the new Belgian star Eddy Merckx rose to prominence, but he still grabbed second in the 1967 Paris–Roubaix, won La Flèche Wallonne in 1968, and took a stage of the 1969 Tour de France. His rivalry with Eddy Merckx reached the height of sabotage of Merckx in the world championships in 1969.
Van Looy was also a star on the track, winning 11 Six-day races. His first came in Brussels in 1957, his last in Antwerp in 1968. For nine of these victories, he was paired with DutchmanPeter Post.