The 1921 Giro di Lombardia was the 17th edition of the Giro di Lombardia cycle race and was held on 10 November 1921, on a course of . The race started and finished in Milan. The race was won by the Italian Costante Girardengo, who reached the finish line at an average speed of , preceding his compatriots Gaetano Belloni and Federico Gay.
67 cyclists departed from Milan and 32 completed the race.