Oranje were attempting to build on their 5-2 victory over Bosnia and Herzegovina in their opening UEFA Nations League fixture.
However, the Euro 2024 semi-finalists had to make do with a 2-2 draw against the hosts from that tournament having let slip a first-half lead.
Manchester United centre-back De Ligt inadvertently contributed to each of Germany's goals, a misplaced pass leading to their equaliser and a poor clearance playing a part in their second.
Those incidents followed the former Juventus and Bayern Munich man producing a similar performance in the seven-goal thriller at the weekend.
Koeman substitutes De Ligt at half time
Although De Ligt played the full 90 minutes versus Bosnia and Herzgovina, Koeman was not prepared to keep the 25-year-old on the pitch against Germany.
United's new £42m signing was replaced at half time by Brighton & Hove Albion's Jan Paul van Hecke, who helped Netherlands avoid conceding further goals after the break.
Speaking to NOS after the game, Koeman acknowledged that he withdrew De Ligt in order to prevent him from making further mistakes that may dent his confidence.
He said: "Of course I would rather have kept [Matthijs de Ligt] on the pitch. It just looks like he is now in a period where all his mistakes are being punished.
"I gave him a new chance today but eventually I protected him by taking him off."
What does De Ligt's immediate future look like?
Having failed to feature for a single minute of Netherlands' run to the last four of Euro 2024, De Ligt has not delivered to his full capabilities since joining United.
United have conceded four goals during the 91 minutes plus added-on time that De Ligt has featured thus far, while a further four goals have come during 135 minutes for Netherlands.
While he started against Liverpool before the international break, De Ligt faces the realistic prospect of being dropped for Harry Maguire when United face Southampton on Saturday.
Games against the likes of Barnsley in the EFL Cup and FC Twente in the Europa League could be viewed as opportunities for De Ligt to get back on track.