Chiefs started with only one defeat in their last five matches in all competitions, with Zesco’s last showing ending in a 1-1 with TP Mazembe with their campaign in off-season mode.
Furthermore, the two sides made two changes each from their last encounters, with Willard Katsande shrugging off an injury to return and captain Chiefs in place of George Maluleka.
In front of a sold-out stadium, Zesco wasted little time asserting their dominance when Jesse Were flashed a good chance wide two minutes from kickoff.
The recently crowned Zambian champions were ahead on 24 minutes as Lazarus Kambole finished off a move created by Rahim Osumanu.
However, the ante was doubled when Teenage Hadebe brought down Were, prompting the referee to award a penalty which the Kenyan striker converted on the half and hour mark.
Closing in on halftime, Khama Billiat combined well with Katsande from the edge to the box to get a shot away that cracked off the post.
Chiefs' Zimbabwean playmaker were eventually on the score-sheet as he finished off a nice move two minutes to halftime to give the Amakhosi a crucial away goal.
Ernst Middendorp made a tactical switch at the start of the second half, with Godfrey Walusimbi making way for Dumisani Zuma in an all-out offensive approach.
The 2016 CAF Champions League semi-finalists weren’t bothered, and instead went further ahead after Were peaked off good work from Kambole on 52 minutes to complete his brace.
Chiefs hoped to have quickly reduced the deficit once again, but Billiat was denied a double as his effort was ruled for offside
Dangerman Kambole missed an absolute sitter to make it 4-1 when a sign of overconfidence resulted in dismal final execution.
The Amakhosi threw their last dice forward as Billiat went close with a close-range effort that forcing Jacob Banda to a make a good save as Zesco saw out the remaining stages to claim a good win.
The next match for the Soweto giants is a trip down south to meet AmaZulu in the Absa Premiership on Wednesday.
Chiefs: Vries, Hadebe, Booysen, Cardoso, Walusimbi, Katsande, Ntiya-Ntiya, Ekstein, Manyama, Billiat, Castro.
Subs: Bvuma, Ngezana, Zulu, Parker, Moon, Andrianarimanana, Nsthangase, Zuma.