Brescia's relegation from Serie A was confirmed after a 3-1 defeat away at fellow strugglers Lecce on Thursday (AEST).
Daniele Dessena gave Brescia hope after Gianluca Lapadula's first-half double at Via del Mare, but Riccardo Saponara's 70th-minute goal ended any hopes of a comeback.
With Genoa defeating Sampdoria 2-1 in the Derby della Lanterna, Brescia were left 12 points adrift of safety with three games left.
It is the 13th time Brescia have been relegated to Serie B, more than any other team.
Lecce occupy the only remaining unconfirmed relegation spot but are only four points behind 17th-placed Genoa.
Brescia were promoted from Serie B as champions in 2018-19 but have returned to the second tier after a single season in the top flight.