After a fairly tense, low-key first half, Smalling headed home from a corner just moments after the restart to completely change the complexion of the game.
Minutes later he helped his centre-back partner get on the scoresheet, as Gianluca Mancini turned home his looping cross with an exquisite volley.
Edin Dzeko then rounded off the scoring on 66 minutes - in a game where both he and Nicolo Zaniolo had goals ruled out by officials.
Back in action for the first time in two weeks, it was a slightly rusty start for Paulo Fonseca's side - with clear-cut chances few and far between.
In the second half the Giallorossi came roaring out, however, and had the ball in the back of the net four times in a 15-minute spell. One of those was ruled out, but the other three counted - deciding the game in accelerated fashion.
Smalling's opener was perhaps slightly fortuituous - his header being deflected beyond Brescia goalkeeper Jesse Joronen - but there was little lucky about Mancini's strike, a glorious first-time volley that any striker would have been proud of.
When Smalling put his head to yet another corner soon after, it was Dzeko who read the situation to spin on the ball and fire into the unguarded net.
The Giallorossi are back in action on Thursday, as they face Istanbul Basaksehir in a crucial Europa League encounter.
Their next Serie A engagement sees them travel to face Verona on Sunday.
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