Zamalek's Ghanaian striker Junior Agogo scored his second league goal to break the deadlock in the first-half.
ENPPI's equalizer hopes were dealt a major blow shortly afterwards when striker Ahmed Raouf received a straight red card for retaliation.
Given their numerical disadvantage, ENPPI should have tightened their defense to stand any chance of leveling the score.
But they naively pushed forward, leaving huge gaps at the back. Consequently, Zamalek managed to ensure the victory with three second-half goals from Al-Safti, Ahmed Magdi and Sherif Ashraf.
ENPPI scored a consolation through veteran midfielder Abdullah Ragab three minutes from time.
The convincing win put Zamalek, who atoned for their disappointing 1-0 defeat to Gaish last week, in second place of the table with 16 points, just one behind leaders Petrojet, who played an extra match.
ENPPI, who suffered their second defeat of the season, slipped to third spot on 14 points.
Left-back Abdul-Aziz Tawfiq came close to putting ENPPI ahead as early as the third minute but his angled shot from the edge of the area went just wide of the post.
Tawfiq's early attempt was ENPPI' sole effort during the first half as Zamalek gained complete control over the game afterwards.
ENPPI midfielders failed to accomplish their defensive duties, giving too much space to Zamalek men.
Agogo deservedly fired Zamalek in front in the 26th minute when he rose above his marker to receive a free-kick with a backward header that found its way into the net.
The former Nottingham Forest man exerted lots of efforts to make an impact in order to dampen concerns over his commitment to the five-time African champions.
Matters went from bad to worse for ENPPI as Raouf received his marching orders for a studs-up lunge on combative defender Al-Safti, who tumbled over him few moments earlier.
Floodgates Opened
Zamalek ran riot in the second period as ENPPI had a match to forget.
Combative defender Al-Safti doubled Zamalek's advantage six minutes after the break when he connected with a right-wing corner to head home at the near post.
Defensive midfielder Ahmed Magdi scored a rare goal in the 74th minute when ENPPI keeper Mohamed Amer failed to deal with his low shot.
Substitute Sherif Ashraf put the icing on the cake ten minutes from time after a one-on-one confrontation with Amer.
Ragab notched a late consolation when he fired in from close range after a goal-mouth scramble.