A derby awaits New York Red Bulls, while Western Conference rivals LA Galaxy and Seattle Sounders are set to lock horns.
After a three-game road trip, New York Red Bulls cannot wait to get back home as they look to maintain their perfect derby record in MLS.
The Red Bulls completed a run of three consecutive away league matches with a 1-1 draw against Montreal Impact on Wednesday - a performance striker Mike Grella claimed exhibited "a little bit of maturity".
The previous two away fixtures had seen the Red Bulls overcome Philadelphia Union and Orlando City.
But with Jesse Marsch's men finally heading back to Red Bull Arena for a league fixture for the first time since July 11 - although their road trip was broken up by home games in the US Open Cup and International Champions Cup - they are keen to give their fans a win over local rivals New York City.
The first two New York derbies ended with the Red Bulls on top, Marsch's side winning the inaugural match 2-1 at home before a 3-1 triumph at Yankee Stadium.
"I can't wait to get back home and see the fans and see the field," Lloyd Sam said, after scoring the equaliser against the Impact.
"I'm really excited about that game; it's a great one to get back to."
City will enter Sunday's New York derby with just one win in their past four matches and on the back of a 3-2 loss at home to Montreal on Saturday.
Defence has been the problem for City, with Jason Kreis' side without a clean sheet in six matches.
The New York derby will complete the weekend's action, following on from LA Galaxy's high-profile clash with Seattle Sounders.
In a rematch of the 2014 Western Conference Final, which Galaxy won on away goals before going on to lift the MLS Cup, Seattle enter in poor form with four straight defeats in the league, although they drew 1-1 at Vancouver Whitecaps in the CONCACAF Champions League (CCL) on Wednesday.
On Saturday, the Whitecaps will take on another club involved in the CCL in midweek in Real Salt Lake, who won 1-0 at Municipal of Guatemala.
Portland Timbers and Chicago Fire will start the round on Friday, before Toronto FC host Sporting Kansas City and Philadelphia visit Orlando on Saturday.
In other Saturday fixtures, the Impact host DC United, Houston Dynamo take on San Jose Earthquakes and Columbus Crew travel to Colorado Rapids.