It is rather strange that despite being next-door neighbours both countries last clashed at full international level in a 2004 Nations Cup quarter-final in Tunisia with the Malians winning 2-1.
The result of this game is crucial for either side in a group that many would bet on four-time champions Ghana to come through with debutants Botswana making up the numbers.
In the absence of Mahamadou Diarra and Frederic Kanoute, the Barcelona midfielder Seydou Keita and Panathiniakos central defender Cedric Kante Mali have to champion youngsters like Samba Diakite, Samba Sow and El Hadj Mahamane Traore.
Keita will be the main attraction for a very youthful Mali team in Gabon and he insisted that it is the whole team and not he alone who could beat Guinea.
“It will be a very difficult game but we have often enjoyed the luck against Guinea at this tournament,” said the Mali skipper.
“But this is a very different tournament in many ways. First, Mali are here with a very young team and also this will be our opening match in this competition.”
He added: “It’s a big personal responsibility because I’m one of the most experienced players in the team now and must therefore lead by example.
“But at the same time, Seydou alone cannot beat Guinea. We must respect the other team and play as a team to win.”
Guinea have also undergone changes but in September they recalled skipper Pascal Feindouno and big defender Bobo Balde and now the Syli National are a blend of young and experienced campaigners.
The Guineans have been more successful than Mali in the competition recently as they reached the quarter-finals in 2006 and 2008.
Their regional rivals crashed out in the group stages at both the 2008 and 2010 tournaments.
French coach Michel Dussuyer has endeared himself to the country on his return after his team upset star-studded Nigeria to qualify for this championship.
However, the former Benin coach has insisted that feat is now history and his team must preoccupy themselves with the task ahead.
“It was great to finish ahead of Nigeria. Guineans were proud of the team, but all that is now in the past,” said no-nonsense Dussuyer, who is missing Kevin Constant after the star midfielder chose club ahead of country.
“We therefore have to continue to work hard, give our 100% always, because we are not in an easy group.
“Our first objective is to get past the first round. Ghana and Mali will be our major rivals, but we will also not take for granted Botswana, who were the surprise team in the qualifiers.”