Egypt, winner of the last three Nations Cup tournaments, have picked up just a single point from their first two qualifiers and face a battle to reach the finals.
Their woes were replicated by Algeria and Nigeria, who also suffered surprise defeats, and Ghana, held to an unexpected home draw.
Algeria went down 2-0 away at the Central African Republic, who won only their second ever qualifying match, while Nigeria were beaten 1-0 away in Guinea just two days after FIFA lifted a suspension they had imposed on them.
World Cup quarter-finalists Ghana were held to a goalless draw at home by Sudan in which key striker Asamoah Gyan was sent off.
A long range shot from Moussa Maazou earned Niger their biggest ever win in a competitive international, capitalising on a blunder at the back by Egypt's makeshift left back Mohamed Abdelshafi to score after 33 minutes.
It leaves Egypt three points behind group leaders South Africa, who they face next away in March. Bafana Bafana drew 0-0 away in Sierra Leone on Sunday.
Eude Dagoulou and Hilaire Momi scored in the final 10 minutes for the first competitive win for the Central African Republic since 1973 to leave Algeria bottom of the Group D standings.
Algeria, who were at the World Cup finals in June, have now won just two of 14 matches played this year.
Nigeria turned in a lacklustre performance in Conakry, seeming affected by the withdrawal of several key players and the uncertainty over whether the game would go ahead.
Nigeria had been suspended last Monday by FIFA because of political interference in the running of their football federation but had the ban temporarily lifted on Friday.
The Cape Verde Islands are unexpected leaders in Group A after a goalless draw in Zimbabwe on Sunday, keeping up a day to remember for the continent's smaller footballing nations.
But there was one heavyweight with a reason to smile. Tunisia, who had a horror start to the qualifying campaign, won 2-1 away in Togo with Amine Chermiti scoring an 83rd minute winner to move them to within three points of the top in Group K.
The next round of qualifiers are set for March. The 11 group winners, plus the top three runners-up qualify for the finals, which are being co-hosted by Equatorial Guinea and Gabon.
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