The Hammers hosted Bristol City in the third round of the FA Cup, with David Moyes naming a strong starting XI.
It took West Ham just four minutes to find the back of the net, with two of their stars combining for an early opener.
Paqueta, sitting deep in midfield, found Jarrod Bowen with an excellent pass before the forward rounded the goalkeeper and scored.
However, just ten minutes later, the Brazilian was taken off after he appeared to pull up with an injury.
Divin Mubama came on to replace him but West Ham fans will be left worried about the fitness of their star midfielder.
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Paqueta pulled up during the warmup prior to the Hammers' 2-0 win at Arsenal, although played 33 minutes before being substituted.
He was then left out of their squad for the 0-0 draw at home to Brighton and made his return to the side on Sunday afternoon.
West Ham were handed another blow as Mavropanos was also forced off before half-time after landing awkwardly on the pitch.
Hammers fans vented their frustrations on social media as one took to X to say: "Paqueta gone off because he started for what, Mavropanos clattered twice in two minutes and gone off. What a load of s****."
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"F****** hell. Is this competition worth it? Two massive injuries in one half! Won't be surprised if we lose more players here," added a second.
A third questioned: "Any f****** chance. Wtf is going on with our injuries man."
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"West Ham should have rested the starters. 2 injuries," added a fourth as the Hammers deal with further fitness issues.
Tommy Conway ruled out Bowen's opening goal to seal a 1-1 draw for Bristol City and set-up a replay at Ashton Gate.
At full-time, Bowen had to be helped off the pitch as he too appeared to suffer an injury, this time his ankle.
Moyes' side will be safe in the knowledge that they have just one game left to play this month due to the Premier League winter break.
They travel to Sheffield United on Sunday 21 before hosting Bournemouth 11 days later in a busy February schedule.
West Ham are currently without Mohammed Kudus due to him being called up to the Ghana squad for the African Cup of Nations.