Inter had made a good start to the 2014-15 season, winning two and drawing two of their opening four fixtures.
But they fell apart against Cagliari as Swede Ekdal made the most of captain Yuto Nagatomo's red card at the San Siro.
Inter's Japanese full-back Nagatomo saw red for a second bookable offence in the 27th, paving the way for Ekdal to take centre stage.
The 25-year-old put Cagliari ahead in the 29th minute and he completed his treble haul before half-time as Zdenek Zeman's men ended their three-game winless streak.
It could have been a lot worse for Inter after Nemanja Vidic conceded a first-half penalty but goalkeeper Samir Handanovic saved Andrea Cossu's effort.
In a repeat scoreline of their last meeting in February, Sampdoria emerged victorious courtesy of Manolo Gabbiadini's 75th-minute free-kick.
The away win preserved Sampdoria's unbeaten start to the season after five matches, four points adrift of leading duo Juventus and Roma.
Callejon's 28th-minute strike handed Napoli a 1-0 win - ending the club's run of three games without a victory.
Napoli's triumph sent Sassuolo to the foot of the table.
10-man Milan earned a share of the spoils at Cesena after defender Adil Rami cancelled out Davide Succi's first-half opener.
Despite playing the final 17 minutes with a man less following Cristian Zapata's dismissal, Milan held on for back-to-back draws.
