The Liverpool forward had earlier seen a
seventh-minute penalty saved by Egypt keeper Gabaski.
Chelsea’s Edouard Mendy denied Mohanad Lasheen to give Mane the chance to win it in Yaounde’s Olembe Stadium.
Gabaski had made three good saves from Senegal’s Bamba Dieng in extra time.
All four of Egypt’s knockout games at the tournament went the distance, and the North Africans had beaten Ivory Coast and hosts Cameroon on spot-kicks en route to the final.
Gabaski had already saved four penalties at the tournament by the time the match went to a shootout, but on this occasion the 33-year-old ended on the losing side.
Egypt were the first to err when centre-back Mohamed Abdelmonem saw his penalty hit the left-hand upright and bounce away – but Gabaski immediately denied Bouna Sarr.
However, Lasheen saw his effort saved and Mane won it with an emphatic finish into the bottom left-hand corner.
That meant his Liverpool team-mate Mohamed Salah did not even have the chance to take a penalty, with the Pharaohs captain set to go fifth for his side.
Senegal had previously lost two Nations Cup finals, finishing runners-up in 2002 and 2019.
Mane and the rest of the Teranga Lions squad will celebrate their victory, while Egypt will soon have a chance for revenge, with the two sides meeting again next month in a two-legged play-off for a spot at the 2022 World Cup in Qatar.