Bruce Arena's side currently top Group Eight and lead their opponents by two points, having played a games less.
Galaxy currently sit fourth in the MLS Western Conference and have been in formidable form in the Champions League, winning both of their games so far without conceding a goal, while Cartagines have a mixed record.
The Costa Rican side have won, drawn and lost once in their group, with that defeat coming against the Galaxy in August.
In Group Seven, Tijuana can also make sure of their progression with just a point, as they face winless Victoria.
The Mexican side are unbeaten in the competition so far, although defeat to the Honduran side would allow Firpo to leapfrog them when they play their final group game in October.
Three points for either Alajuelense or Sporting San Miguelito when the pair meet would move them level on points with Group Four leaders America, with the Costa Rican side Alajuelense having played a game less than their two group rivals.
Cruz Azul will be favourites going into their Group Three clash with bottom side Valencia, having won both their games so far. While Valencia have no hope of qualification, the Liga MX outfit can move three points clear at the top and bolster their hopes of progression.
Heredia can book their place in the next stage with a win over Group Five's bottom side Montreal Impact while Olimpia will look to keep their hopes of progression alive from Group Two with victory over Real Esteli.
MLS outfit Houston Dynamo will leapfrog Arabe Unido to the top of Group One with a win against bottom side W Connection of Trinidad and Tobago after the Americans beat the leaders 2-1 last month.
In Group Six, Comunicaciones need to win both their remaining games, starting against Caledonia AIA, if they are to catch leaders Toluca.
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