The 2021 Tre Valli Varesine was the 100th edition of the Tre Valli Varesine road cycling one day race, which was held in the Lombardy region of northwestern Italy on 5 October 2021.

This edition was the race's first in the UCI ProSeries; the 2020 edition was expected to feature in the inaugural UCI ProSeries but was cancelled due to the COVID-19 pandemic.

The 196.74-kilometre (122.25 mi) race began in Busto Arsizio, with the first 46.5 kilometres (28.9 mi) of the race heading north and entering midway through the short circuit in and around Varese.

[5] Following this, the race concluded with two laps of a longer 25.72-kilometre (15.98 mi) circuit that added the Morosolo and Casciago hills in between Montello and Casbeno.

There were five non-starters from five separate teams (Amore & Vita, Androni Giocattoli–Sidermec, Astana–Premier Tech, Groupama–FDJ, and Israel Start-Up Nation).