Ex-Man United defender Smalling’s return from a knee injury was the only positive note for Paulo Fonseca’s side whose European ambitions next season have been dented.
Joao Pedro set up Charalampos Lykogiannis to put Cagliari ahead after just four minutes in the Sardegna Arena.
Carles Perez pulled Roma level before the half hour mark but Razvan Marin and a Joao Pedro header either side of the hour restored the hosts’ advantage.
Smalling played for an hour before being substituted by Bryan Cristante.
A Federico Fazio header revived Roman hopes with 20 minutes to go but the visitors were unable to find the equaliser.
“Smalling played a very good game, the team is a lot more secure with him and it was important to let him play at least for a while so as to have him for Manchester,” said Fonseca.
“Today it was important that he played at least 45 minutes – and in the end he played 59.
“That’s positive heading into the game in Manchester.
“We weren’t able to give a runout to all of the players that are just back from injuries, but the key thing was to be able to get Smalling and Leonardo Spinazzola back out there.”
Roma’s Champions League ambitions are effectively over as they are 10 points behind fourth-placed Atalanta, who play Bologna later on Sunday, with five games to play.
They are also three points behind city rivals Lazio, who occupy the final Europa League berth, and have played two games fewer.
Cagliari boosted their hopes of Serie A survival with a third straight win to move out of the relegation zone.
Now in 17th position, they are equal on points with Torino just ahead and Benevento below them.
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