After drawing 1-1 in their first-leg playoff against Syria on Thursday the Socceroos will now need either a win or a 0-0 draw in the second leg in Sydney on Tuesday to advance to the final playoff, where they will meet the fourth-placed North and Central American side.
The US currently sit fourth in the CONCACAF standings, just one point behind third-placed Panama, with two games remaining - the top three sides will book an automatic spot in next year's World Cup.
With Mexico already through to Russia as the top-placed side and Costa Rica certain to join them, it's essentially a three-way battle between Panama, the US and Honduras to clinch third sport in the group.
The US will meet Panama on Friday (Saturday AEDT) and Trinidad and Tobago on Tuesday (Wednesday AEDT).
They will likely need a win against the Panamanians followed by a victory or a draw at Trinidad and Tobago to book a ticket to Russia.
Failure to qualify automatically however, would mean they're likely to face the Socceroos in the cut-throat CONCACAF-AFC two-leg playoff in November.
Should the US snatch third place in their group, the Socceroos will face either Panama or Honduras.
Speaking ahead of the match against Panama, US teenage sensation Christian Pulisic is hoping his side will avoid further playoffs
"We need three points bad," Pulisic said. "We want to come out flying."
Key defender Omar Gonzalez seemed to agree, telling the media: "We all understand what needs to be done, how we need to step out on the field, the focus that we need to have, the match intensity we need to have throughout the 90-minutes plus."
Bruce Arena's side are winless in their last three qualifiers, including a defeat at home to second-placed Costa Rica, the first time in which the Americans have lost two home games in the same World Cup cycle since 1957.
"It's a big occasion," Arena said of the match at hand. "I don't think I need to lecture our players on the significance of the game."