Smalling collided with Klaas Jan Huntelaar as the Dutch striker headed home his side's second goal in as many minutes, just before the hour mark. With both players left lying flat out on the Wembley pitch, Holland's celebrations were curtailed and a worrying break in play ensued. After treatment, Huntelaar was able to walk off the pitch clutching a bloody nose but the England and United centre-back had to depart the arena on a stretcher.
Phil Jones was Smalling's replacement, albeit at right-back with Micah Richards moving into the middle, and the versatile Red later claimed an assist when his first-time pass played in club colleague Ashley Young to clip home England's injury-time equaliser. But just when caretaker manager Stuart Pearce thought he'd marked his debut in the hotseat with a dramatic 2-2 draw, Arjen Robben curled Holland's exquisite winning goal past Manchester City goalkeeper Joe Hart.
Former Chelsea winger Robben also grabbed the opener with a stunning solo surge from inside his own half. Current Chelsea centre-back Gary Cahill was England's other scorer, cutting Holland's lead to 2-1 late on before Young levelled the scores with his fourth goal in five international appearances.
The latter was the only United man to complete the full 90 minutes - Danny Welbeck started up front but was replaced in the second half when former Reds striker Fraizer Campbell came on to earn his first senior cap.
The England quartet were not the only Reds who lost a midweek international at home. Jonny Evans played a full match for Northern Ireland as they were beaten 3-0 in Belfast by Norway.