The title holders' Portuguese coach Jose Mourinho opted to rest several regular players to keep them fresh for Wednesday's crucial clash away to Barcelona in the second leg of the Champions League semi final.
Atalanta took a surprising lead after five minutes when Simone Tiribocchi broke the offside trap to race clear and fire home from inside the area.
Inter's in-form striker Diego Milito leveled the score on 24 minutes with a superb lob after making the most of a mistake from Atalanta defender Paolo Bianco.
Kenyan midfielder McDonald Mariga gave them the lead 10 minutes before the break with a powerful shot from inside the area.
Left-back Cristian Chivu wrapped up the win with 13 minutes remaining helped Inter go two points clear of AS Roma.
However, the capital side could regain their lead on top if they beat Sampdoria on Sunday.
The match's goals