Draxler did not even last a minute in Schalke's 1-0 win over Augsburg in the Bundesliga, limping off after seemingly aggravating the hamstring injury he first suffered playing for Germany at the start of September and has been nursing since.
Although Schalke went on to win thanks to Klaas-Jan Huntelaar's first-half strike, it was a tough night for Di Matteo and his men, after they watched their star playmaker depart the field after just 10 seconds and then struggled to break down a team that have now lost four straight away games.
"It's unpleasant for the whole team, especially when it happens right at the beginning of a game," said Schalke defender Jan Kirchhoff, who started his first game since hurting his knee in August.
"Julian is an important part of the team. We struggled after that and needed a bit of time to recover.
"Augsburg also made it difficult for us though. They moved the ball around well."
Di Matteo, who oversaw his third win in four matches in all competitions since taking over at Schalke, was left frustrated by how Draxler's injury, on top of the likes of Joel Matip (thigh) and Jefferson Farfan (knee), is hindering his ability to initiate changes at the Veltins-Arena.
"Losing Julian Draxler extends our injury list even further. It’s a real blow," the coach said.
"We're still waiting on a more concrete diagnosis.
"We can still improve our playing style but you can't forget that we're missing nine players at the moment. We have to deal with that first of all."
Kirchhoff urged the fans to be "patient" as Schalke learn Di Matteo's style, after the Italian replaced Jens Keller last month, but captain Benedikt Howedes was less positive, claiming the North Rhine-Westphalia-based side need to catch up fast.
"It wasn't pretty but all that counts is the three points," Howedes said.
"Ultimately, we can be happy with that, dust ourselves off and look ahead.
"We didn't do much of what the manager has asked of us. Every individual has to take responsibility for that and keep working hard on their game."