Pagani began racing motorcycles in 1928. By the late 1940s he was racing cars as well as motorcycles, winning the Pau Grand Prix in both 1947 and 1948 — a prestigious non-championship Formula One event held in the French Basque region — which demonstrated genuine ability in single-seater machinery at a time when the two disciplines overlapped.
The 1949 season was Pagani's defining achievement. When the FIA introduced the first Motorcycle Grand Prix World Championship, Pagani entered simultaneously in two classes for two different manufacturers.
In the 125cc class he rode for Mondial. He won the Swiss Grand Prix with fastest lap and won the Dutch TT with fastest lap, then finished fifth at the Nations Grand Prix in Italy. His three scored results totalled 27 points and secured the inaugural 125cc World Championship — the first motorcycle world title ever awarded under the FIA framework.
In the 500cc class he rode for Gilera. He won the Dutch TT with fastest lap and the Nations Grand Prix with fastest lap, finished third at the Ulster Grand Prix, and placed fourth at the Swiss Grand Prix. His total points across all results exceeded those of the eventual champion, Les Graham of AJS. However, the championship rules counted only each rider's best three results from six rounds. Pagani's three counting scores — two wins and a third — were narrowly edged by Graham's two wins and a second. Pagani was officially classified runner-up in the 500cc class despite being the higher-scoring rider in aggregate.
Pagani continued in the Motorcycle World Championship through 1955. He rode for Gilera in the 500cc class through 1953, finishing fourth in the championship standings in 1950. In 1951 he competed for Mondial in the 125cc class, placing tenth. He then moved to MV Agusta for 1954 and 1955, scoring points in both seasons. His career totals in Grand Prix motorcycle racing record 22 starts, 4 wins, 11 podiums, 4 fastest laps, and 93 points across all classes.
After retiring from active competition, Pagani became team manager of the MV Agusta factory motorcycle racing programme — the sport's most successful operation through the late 1950s and into the 1960s, dominating multiple classes simultaneously.
Car racing was a parallel but secondary strand of Pagani's career, pursued alongside his motorcycle activities throughout the late 1940s and early 1950s. In addition to his Pau victories, his sole Formula One World Championship appearance came on 4 June 1950 at the Swiss Grand Prix at Bremgarten, driving a Maserati 4CLT/48 — one of the older 4-cylinder machines — entered by Scuderia Achille Varzi. He finished seventh, scoring no championship points. The 1950 championship entry list records his car as one of the Maseratis driven by privateer entrants at the Swiss round. During the same season he finished fourth in the Modena Grand Prix driving a Simca-Gordini. In 1952 he finished second in class at the Mille Miglia in an OSCA.
Nello Pagani died in Bresso, Lombardy on 19 October 2003, eight days after his 92nd birthday. He was the father of Alberto Pagani, who also raced as a Grand Prix motorcycle competitor. Pagani's permanent place in history rests on winning the first motorcycle world championship under the modern FIA framework, and on the statistical near-miss of the 500cc title in the same year — a double that the counting-results rules of 1949 prevented him from achieving despite his aggregate superiority.