A new manager is on board to steer Santos back on course in group B when they host Cameroon's Coton Sport in Cape Town.
Coton Sport are in Group B's driving seat
David Notoane has taken charge of the South African club, replacing Boebie Solomons who was sacked after a 4-0 defeat to Coton three weeks ago.
Santos are bottom with three points and only a win can give them a realistic chance of reaching the final.
Only the winners of each group will play in the final of the Confederation Cup, which is in its inaugural year.
Coton Sport lead the group with five points.
A win will put them in a comfortable position for a second successive final in African competition.
Last year the Cameroonian side were runner-up in the last edition of the Caf Cup final.
The Caf Cup was merged with the Cup Winners' Cup to form the Confederation Cup.
Another Cameroonian side Sable Batie are second in Group A with four points but are tied with Ghana's Hearts of Oak.
Both sides have the chance of topping the group on Sunday, should Santos beat Coton.
In Group B, Rangers of Nigeria could consolidate their lead if they defeat Sudan's Al Hilal in Omdurman.
Rangers lead the group with six points.
Hilal, who lost 4-0 when both sides met in Enugu last month, have three points.
Asante Kotoko also have six points as they travel to play Petro Atletico in Angola.
Petro have three points and a win could salvage their campaign.
Confederation Cup games
Saturday 16 October
Group B - Santos v Coton Sport, Cape Town, 1300 gmt
Group A - Rangers v Al Hilal, Omdurman, 1900 gmt
Sunday 17 October
Petro Atletico v Asante Kotoko, Luanda, 1500 gmt
Hearts of Oak v Sable Batie, Accra, 1600 gmt