He competed in the FIM Grand Prix motorcycle racing world championships from 1949 to 1958, most prominently as a member of the Gilera factory racing team where he won the 1950 and 1952 500cc world championships.

He debuted in the Grand Prix motorcycle World Championship in 1949 aboard a Moto Morini, in the 125cc class.

In 1950, Masetti won the Grands Prix of Belgium and the Netherlands and defeated Geoff Duke for the 500cc World Championship.

In 1953 he raced in the 250cc class for NSU, but an accident at Imola prevented him from taking part for much of the season.

1949 point system: Points system from 1950 to 1968: (key) (Races in italics indicate fastest lap) 1949  L. Graham 1950  U. Masetti 1951  G. Duke 1952  U. Masetti 1953  G. Duke 1954  G. Duke 1955  G. Duke 1956  J. Surtees 1957  L. Liberati 1958  J. Surtees 1959  J. Surtees 1960  J. Surtees 1961  G. Hocking 1962  M. Hailwood 1963  M. Hailwood 1964  M. Hailwood 1965  M. Hailwood 1966  G. Agostini 1967  G. Agostini 1968  G. Agostini 1969  G. Agostini 1970  G. Agostini 1971  G. Agostini 1972  G. Agostini 1973  P. Read 1974  P. Read 1975  G. Agostini 1976  B. Sheene 1977  B. Sheene 1978  K. Roberts 1979  K. Roberts 1980  K. Roberts 1981  M. Lucchinelli 1982  F. Uncini 1983  F. Spencer 1984  E. Lawson 1985  F. Spencer 1986  E. Lawson 1987  W. Gardner 1988  E. Lawson 1989  E. Lawson 1990  W. Rainey 1991  W. Rainey 1992  W. Rainey 1993  K. Schwantz 1994  M. Doohan 1995  M. Doohan 1996  M. Doohan 1997  M. Doohan 1998  M. Doohan 1999  À. Crivillé 2000  K. Roberts Jr. 2001  V. Rossi 2002  V. Rossi 2003  V. Rossi 2004  V. Rossi 2005  V. Rossi 2006  N. Hayden 2007  C. Stoner 2008  V. Rossi 2009  V. Rossi 2010  J. Lorenzo 2011  C. Stoner 2012  J. Lorenzo 2013  M. Márquez 2014  M. Márquez 2015  J. Lorenzo 2016  M. Márquez 2017  M. Márquez 2018  M. Márquez 2019  M. Márquez 2020  J. Mir 2021  F. Quartararo 2022  F. Bagnaia 2023  F. Bagnaia 2024  J. Martín