Sadio Diallo scored the first two followed by Abdoul Razzagui Camara and Ibrahim Traore, all before half-time, and two late efforts from Mamadou Dioulde Bah and substitute Naby Soumah.
The five-goal winning margin equals Ivory Coast's 6-1 win over Ethiopia at the 1970 edition in Sudan and also provides Guinea with their first points of the tournament.
But Guinea might have set a new mark had Pascal Feindouno's 55th minute effort that crossed the line after hitting the underside of the crossbar been awarded.
Dipsy Selolwane scored for Botswana from a twice-taken penalty but the Nations Cup debutants played the entire second half down to 10 men after Patrick Motsepe was sent off for a horror tackle.
Diallo scored the first two goals in almost similar fashion, powering home the ball from close range after a cross from the left.
In between his two efforts, Selolwane netted a penalty for Botswana after Guinea's goalkeeper Naby Yattara had committed a panicky tackle on Jerome Ramatlhakwana.
But Selolwane only scored at the second attempt after Yattara had stopped the first but been correctly adjudged to have moved forward off his line before the ball was struck.
Camara's goal, in only his second appearance, came from the left again but instead of passing square he hit the ball home from a tight angle to make it 3-1 in the 42nd minute.
Then Motsepe was dismissed for a studs-up challenge on Feindouno and from the subsequent free-kick Traore scored off the upright.
Two more goals came in the last six minutes, first from a 25-metre rocket from Bah that was deflected off Mogogi Gabonamong and finally a shot across the goal from Soumah.
There were also some horror misses from Guinea who might have doubled their winning margin, no more so than when Ibrahima Conte went around the goalkeeper but still contrived to miss.
Guinea are back in contention for a quarter-final place after losing their opening game to Mali on Tuesday. Botswana were beaten 1-0 by Ghana in their opening match.
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