The defeat meant the Iranian side, runner-up to Urawa Reds in 2007, cannot advance to the last 16 of the competition while Al Ittihad moved to within two points of second-placed Al Nasr with only one round of group matches remaining.
Al Ghamdi scored three minutes into first-half stoppage time.
Fahad Al Muwallad netted seven minutes from time.
Al Ghamdi then added a third four minutes before the end and Gelmin Rivas completed the rout on the stroke of full time.
Al Ittihad and Sepahan meet again in two weeks' time and Victor Piturca’s team must win again to have any chance of overhauling Al Nasr while the win for the Saudis also meant group leader Lokomotiv will have to wait until Matchday Six before confirming their place in the next phase.