The 21-year-old has been an ever-present in Arsenal's Premier League lineup so far this season but was on the receiving end of some rough treatment by Renan Lodi at the start of Sunday's game.
Nevertheless, Saka contributed to an extremely quick start from Arsenal, providing an inch-perfect cross for Gabriel Martinelli to head home after just five minutes at the Emirates.
However, the England international was not moving at all comfortably in the opening exchanges, although the Arsenal bench did not appear overly concerned at first.
Saka then went down onto the turf with about 15 minutes gone clutching his lower leg, but he was able to carry on for a short while after receiving treatment.
The attacker's contribution did not last long, though, as he was eventually forced off the field to be replaced by countryman Reiss Nelson just before the half-hour mark.
It remains to be seen how serious Saka's injury is, but witnessing him limp off the field will no doubt concern Mikel Arteta and Gareth Southgate until an update is provided.
Prior to coming off the field and heading straight down the tunnel, Saka's cross for Martinelli's header took him up to five assists for the season in all competitions alongside his five goals.
The Hale End graduate will be expected to earn a place in Southgate's World Cup squad should he prove his fitness, and he now has 28 goals and 34 assists to show from 148 games in all competitions.
Arteta was recently quizzed on Saka's unrelenting period of matches, but the Gunners boss insisted that the 21-year-old must want to play up to 70 games a year if he wants to be among the best.
"Look at the top players in the world. They play 70 matches every three days and make the difference and win the game," Arteta told reporters.
"You want to be at the top, you have to be able to do that. And if we start to put something different in the mind of a young player, I think we are making a huge mistake because then [he would] be like, 'no, I don't play now, on astroturf I don't play'. I don't want that.
"I want them to be ruthless every three days. I want them knocking on my door [saying] I want to play, I want to win the game. There is no fitness coach in the world that is going to tell me that they cannot do it because I've seen it.
"Seventy-two games and scored 50 goals. The players that score 50 goals do not play 38 games in the season, it's just impossible."
Arsenal are also without Matt Turner, Oleksandr Zinchenko, Emile Smith Rowe and Mohamed Elneny through injury, although the latter has made a much quicker return to training from his hamstring injury than initially expected.
England begin their World Cup campaign in Group B against Iran on November 21 before tackling the USA and Wales on November 25 and November 29 respectively.