For both players, it was a maiden appearance in the quarterfinals at Roland Garros while 19-year-old Rune became the first Danish man to reach this stage of the French Open.
Rune had enjoyed a fairytale run to the quarters, upsetting Denis Shapovalov in the first round and No. 4 seed Stefanos Tsitsipas in the fourth round, before eventually falling to Ruud.
"A big day for Norwegian tennis because we have also a female player Ulrikke Eikeri who made the finals of mixed doubles today. She's even one step further than me!" Ruud said in his post-match, on-court interview.
"These are the matches that you dream about playing. And hopefully, of course, even the final if it's possible," he continued. "I have to be really focused and bring my A-game in the semifinal."
The Norwegian began the match in an impressive fashion, breaking Rune twice to open up a 5-0 lead in the first set which he eventually won 6-1.
"I started great but then Holger fought back well, raised his level and I had a really tough match in the end there," Ruud said afterwards.
The second set was more evenly balanced, as the two players traded breaks early on before Rune broke Ruud in the last game to level the match.
But by the third set, Ruud seemed to have an answer for everything that the Dane tried; an inch-perfect approach shot was met by Ruud's outstretched backhand while a dropshot only dragged Ruud towards the net.
Throughout the match, Rune had been talking to his box, and when he was broken in the third set, he appeared to shout at his mother who left the court.
"I love my mother and I don't send her away," Rune later clarified to Eurosport. "When I'm frustrated, it can help that either my mother or coach leaves, so I don't have two people to refer to. She also left at some point against Stefanos [Tsitsipas] to give me ease. She controls it, not me."
The set remained finely poised and required a tiebreak to separate the two players. Ruud edged 4-2 ahead and did not lose another point to take the tiebreak and the set 7-2.
Buoyed by this, Ruud regained control as he won 94% of his first-serve points in the fourth and won 6-3, taking the match in three hours and 15 minutes.
The Norwegian will face a resurgent Marin Cilic in the semifinal on Friday.