Edmund had not played a singles match at any of tennis' biggest events since the US Open in 2020, after which he underwent three knee operations before finally making his return earlier this summer.
He was given a very tough draw against French Open finalist Ruud, who is a contender for the title, and came up short in a 6-3 7-5 6-2 defeat in sweltering conditions at Flushing Meadows.
But Edmund should feel encouraged that he is not too far away as he treads the long road back to what he hopes will be a return to the higher echelons of the game.
Ranked as high as 14th in the world in 2018, the year he also made the semi-finals of the Australian Open, Edmund had been troubled by the knee issue for some time before deciding he needed to step away from the court.
The former British number one's big weapon, his thumping forehand, was still very much in evidence as he took on Ruud, but the Norwegian has firepower of his own.
After losing the opening set, Edmund threatened a comeback when he fought back from a break down to make it 5-5 in the second.
But the 27-year-old could not find the dominance on serve that he needed and was ultimately too error prone to really trouble Ruud.
Meanwhile, defending champion Daniil Medvedev made short work of American Stefan Kozlov.
Medvedev, one of five men who could end the tournament at world number one, dropped just six games in a 6-2 6-4 6-0 victory.