Ghana triumphed 6-1 in the first leg of a 2014 World Cup play-off to set up an aggregate victory that prolonged the agony of Egypt, who have not competed at the finals since 1990.
Mohamed Salah converted a 43rd-minute penalty amid an electric atmosphere at the Borg El Arab Stadium and Abdallah Saied doubled the lead four minutes from time with a close-range shot.
Ghana, seeking to qualify for a fourth consecutive World Cup, dominated second-half possession without finding a way past 43-year-old goalkeeper Essam El Hadary.
El Hadary is the lone survivor of the national team of the previous decade that won three straight Africa Cup of Nations titles, but repeatedly failed to secure World Cup qualification.
Egypt have six points after two rounds, Uganda four, Ghana one and Congo Brazzaville are pointless.
The remaining four rounds are scheduled between August and November 2017 with the group winners qualifying for the 2018 World Cup in Russia.
Salah put Egypt ahead with a spot-kick that just avoided the legs of goalkeeper Razak Brimah after Harrison Afful fouled Mahmoud Hassan.
A late counterattack caught out Ghana and a couple of square passes set up Saied to turn and score with a low shot into the corner.
A Farouk Miya goal on 18 minutes gave bottom seeds Uganda a 1-0 win over Congo in Kampala Saturday.
Guinea host the Democratic Republic of Congo in Conakry later Sunday in the last of 10 African matchday 2 World Cup fixtures.