Both sides, who find themselves level on points outside the playoff places, will be looking to get one over the other and launch a late push for post-season football.
Match preview
Nashville kept their slim hopes of securing a top-eight finish in the East alive as they picked up an impressive 2-0 victory over Atlanta United when the two sides squared off at the weekend.
Alex Muyl gave the visitors a dream start at the Mercedes Benz Stadium as he opened the scoring in the fifth minute before Hany Mukhtar doubled the lead with a 76th-minute strike.
This was a much-needed result for Nashville, who had suffered defeat in each of their last 10 matches across all competition — a run which saw them crash out of the Leagues Cup in the group stages after successive losses against Mazatlan and New England Revolution in August.
Head coach B.J. Callaghan will hope that the victory over Atlanta United can serve as a springboard for a strong end to the season as the Boys in Gold look to make a late push for a playoff spot.
Having secured a seventh-placed finish last term, Nashville's underwhelming campaign has been owing to their lack of firepower at the attacking end of the pitch, where they have netted the fewest number of goals in the league so far (28).
Like Wednesday's hosts, Chicago Fire picked up three huge points in their push for a playoff spot last weekend as they secured a hard-fought 2-1 victory over New York Red Bulls at Soldier Field.
New York Red Bulls' midfielder Dennis Gjengaar netted two minutes after the break to cancel out Tom Barlow's 31st-minute opener, but Georgios Koutsias struck in the 75th minute to hand the hosts all three points.
Prior to that, Chicago Fire were on a run of six consecutive games without a win across all competitions, claiming one draw and losing five, including back-to-back defeats against Toluca and Sporting Kansas City in the Leagues Cup, where they finished rock-bottom in Group D back in August.
Frank Klopas's men have picked up 29 points from their 29 MLS matches so far to sit 13th in the Eastern Conference standings, level on points with Wednesday's hosts and four points off ninth-placed DC United in the coveted play-in places.
While Chicago Fire will be looking to continue from where they left off against the Red Bulls and pick up consecutive wins for the first time since June, they journey to Geodis Park, where they have failed to win their previous three visits, losing twice and claiming one draw while conceding nine goals and scoring twice.
Nashville SC Major League Soccer form:
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L
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W
Nashville SC form (all competitions):
L
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W
Chicago Fire Major League Soccer form:
W
L
D
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W
Chicago Fire form (all competitions):
L
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D
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W
Team News
Nashville will be without several players down the spine of the team as Randall Leal (hip), Lukas MacNaughton (ankle) and Jacob Shaffelburg (muscle) continue their spells on the sidelines.
Tyler Boyd continues his long road to full fitness after sustaining an ACL injury back in July, while Mukhtar misses out after crossing the yellow card threshold with his booking against Atlanta United last time out.
As for Chicago Fire, Klopas will be unable to name American defender Mauricio Pineda, who is set to sit out his fourth consecutive game after sustaining a leg injury in August.
He is joined in the club's injury table by fellow countryman Chase Gasper, who has been sidelined since coming off with a severe injury against New England Revolution back in March.
With his winner against the Red Bulls, Gjengaar now has five goals in his last six matches across all competitions and the Greek striker could be rewarded with a starting role on Wednesday.
Nashville SC possible starting lineup:
Willis; Moore, Zimmerman, Maher, Lovitz; Anunga, Godoy, Muyl; Bunbury, Ajago, Surridge
Chicago Fire possible starting lineup:
Brady, Souquet, Teran, Czichos; Haile-Selassie, Herbers, Mueller, Gimenez, Lassiter; Barlow, Cuypers
We say: Nashville SC 2-1 Chicago Fire
Wednesday's result could prove pivotal in their push for a playoff spot and we expect Nashville and Chicago to go all out in search of maximum points. The Boys in Gold have won their last two home games against Klopas's men and we are tipping them to come away with all three points here, albeit by the odd goal.