Smouha was stunned by minnows El-Entag El-Harby on Monday thanks to forward Bassem Morsi, who hit a brace in the 33rd and 79th minutes of the game.
The group leaders failed to impress during the game, giving El-Entag El-Harby, who lie at the bottom of their group, a chance to secure an important win.
Smouha's loss means that second-placed Ahly can top the group if they beat Arab Contractors on Tuesday.
The Alexandrian side are at the top of their group with 29 points, three points ahead of Ahly.
Earlier in the day, Ittihad of Alexandria was held to a goalless draw by Dakhleya, advancing them to third place in the group with 24 points.
(For more sports news and updates, follow Ahram Online Sports on Twitter at @AO_Sports and on Facebook at AhramOnlineSports.)