A first-half brace from Al-Hilal Club forward Mohamed Abdelrahman helped Sudan to a 3-nil advantage at the break of a match which Djibouti hosted at a neutral venue in Marrakech, Morocco.
Ghana overcame Nigeria in Cape Coast with two second half goals from a pairing from Accra-based club Heart of Oaks.
Forward Daniel Afriyie Barnieh scored the first from the penalty spot just after the break before midfielder Seidu Suraj sealed the win in the 86th minute.
The Black Galaxies have a mixed CHAN record - finishing runners-up in two of the first three editions but failing to qualify for the last three tournaments.
Nigeria have been equally inconsistent, qualifying only three times in six attempts and losing 4-0 to hosts Morocco in the 2018 final.
The 2022 African Cup of Nations champions Senegal had winger Meleye Diagne, 19, to thank for the only goal in their win against Guinea.
In the pick of the other games, club commitments meant a weakened South Africa were beaten 2-nil by Angola in Luanda while the other surprise result saw Equatorial Guinea beat Cameroon 1-nil in Malabo. Ivory Coast, meantime, were held to a disappointing goalless draw in Botswana by Burkina Faso.
The second legs will take place between Friday and Sunday.
The expanded 18-team CHAN finals, a tournament for domestic-based players, are scheduled to be held from 8-31 January 2023 in Algeria. The hosts are already assured of a place, as are holders Morocco and Libya after Egypt and Tunisia withdrew from the Northern Group.
Morocco are chasing a third straight title, having defended the trophy at the delayed 2020 finals which were held in Cameroon last year.
CHAN 2022 qualifying - second round first leg results
Western Zone A:
Senegal 1-0 Guinea
Sierra Leone 1-2 Mali
Guinea-Bissau v Mauritania (playing 29 Aug)
Western Zone B
Ivory Coast 0-0 Burkina Faso
Togo 1-0 Niger
Ghana 2-0 Nigeria
Central Zone
Central African Republic 2-1 Congo
Equatorial Guinea 1-0 Cameroon
Chad 1-2 DR Congo
Central Eastern zone
Ethiopia 0-0 Rwanda
Tanzania 0-1 Uganda
Djibouti 1-4 Sudan
Southern Zone
Angola 2-0 South Africa
Botswana 0-1 Madagascar
Malawi 1-1 Mozambique
(Second legs 2-4 September)
