The Dutchman had enjoyed a flawless start to his reign before the visit of Nuno Espirito Santo's side, with three wins and three clean sheets against Ipswich Town, Brentford and Manchester United before the international break.
Victory to nil on Saturday would have seen Slot become the first-ever Premier League manager to win their opening four games with four clean sheets, and Liverpool had not lost to their opponents at home since 1969.
However, Liverpool were unable to pick the Forest lock in front of an agitated home crowd, who witnessed Callum Hudson-Odoi teach the Reds a lesson in ruthlessness with a sublime second-half winner.
After the Reds wasted numerous chances to break the deadlock, Hudson-Odoi cut inside Conor Bradley and let fly with a 20-yard strike, which kissed the inside of the post on its way into the back of the net.
Slot: 'Losing to bottom-half team is a big disappointment'
Addressing the media after suffering his first competitive defeat as Liverpool manager, Slot said that the loss was especially painful due to Forest's regular league positions; the visitors finished 16th in 2022-23 and 17th last term.
However, the Dutchman still praised Santo's side for their organisational skills, while also refusing to rule out the possibility that they could make an unexpected push for elite-level European football as they sit in fourth place, just one point worse off than the Reds.
When asked if his Liverpool "process" had suffered a setback on Saturday, Slot replied: "Not to the process, but it is a big setback. If you lose a home game it's always a setback, especially if you face a team... we never know, maybe they will go all the way to fight for Champions League tickets.
"But normally this team is not ending up in the top 10, so if you lose a game against them that's a big disappointment. Although, they were organised and structured really well today."
Slot refuses to blame international break for Forest loss
Despite boasting 70% possession on home soil and firing 14 shots on the Forest goal, Liverpool lacked the sharpness that they demonstrated before the international break, only managing five attempts on target in total.
However, Slot refused to use the two-week domestic hiatus as an excuse for Liverpool's underwhelming showing, stressing that the "individual performances" from unnamed players were not to the standard he expected.
"It is always difficult to say this, but I don't think it had anything to do with it. Players came back strong and I saw today also a team that wanted to fight until the end," the Reds boss added.
"So it had nothing to do with energy, in my opinion, but we simply had the ball a lot and we had to create from ball possession. If you look at the goals we have scored until now, we also scored quite a few from transition moments, from winning the ball back and then going to transition.
"But the other team played over our press a lot with a lot of long balls, so like I said, we got the ball mostly in our last line. Then it wasn't good enough today because also too many individual performances in ball possession were not of the standards that I am used to from these players."
Liverpool now turn their attention to Tuesday's Champions League opener against AC Milan before returning to Premier League action at home to Bournemouth next Saturday.