Senegal, who reached the quarter finals of the 2002 World Cup, took the lead against Angola but Manchester Utd's Manucho, who is yet to play for his new club, scored two more goals in a spectacular second half fightback.
El-Hadji Diouf's free-kick was turned back across goal by Souleymane Diawara and Newcastle Utd's Abdoulaye Diagne Faye headed Senegal into the lead on 19 minutes but that was as good as it got for Henryk Kasperczak's side.
Manucho equalized five minutes into the second half with another spectacular diving header - clearly one of his specialities - from a right-wing cross from Zé Kalanga before poking home his second of the game and third of the competition in a goalmouth scramble.
World Cup goalscoring hero Flávio Amado headed home the third from Yamba Asha's cross with twelve minutes remaining to seal a famous win for an Angolan side whose international profile is quickly growing.
Manucho may not be about to displace Wayne Rooney or Carlos Tévez from the Manchester Utd first team but has shown superb ability in the air as well as a poacher's instinct for goals and could prove to be one of the best bargains of the transfer window.
The defeat leaves Senegal needing to beat South Africa in their final match to avoid an embarassing early elimination, although they did reach the quarter finals in 2006 despite losing two of their three group matches.
In the day's second match in Group D, 2010 World Cup hosts South Africa lost miserably to Tunisia leaving them on the brink of elimination.
Brazilian-born striker Francileudo dos Santos was the key man for Tunisia, scoring twice and having a big hand in the other goal taken by Chaouki Ben Saada. Santos gave Tunisia an early lead with a fine diving header from an inswinging cross by Ben Saada.
He repaid the compliment after half an hour when his shot rebounded of the post for Ben Saada to tuck the rebound home, before adding his own second two minutes later.
South African defender Nasief Morris was guilty of an extraordinarily careless backpass, intercepted by the unseen Santos who rounded Moeneeb Josephs before passing the ball into the empty net.
Santos might have completed his hat-trick in the second half when Yassine Chikhaoui crossed low from the right but he failed to strike cleanly and the ball could only trickle towards the goal, leaving plenty of time for Bafana Bafana to clear their lines.
South Africa had a small rally in the later stages with Steven Pienaar and Elrio van Heerden both missing the target before a Pienaar shot was deflected home by Katlego Mphela in the 87th minute but unlike their late goal against Angola it couldn't prevent a dispiriting defeat for Carlos Alberto Parreira's side.
The two results leave an awkward situation where Angola and Tunisia could both seal qualification by drawing with each other on Thursday, while Senegal and South Africa will scrap it out in Kumasi hoping there is a victor in the other match.
Results
SENEGAL 1 (A.D. Faye 20') ANGOLA 3 (Manucho 50', 67', Flávio 78')
TUNISIA 3 (Santos 8', 34', Ben Saada 32') SOUTH AFRICA (Mphela 87')
