Raducanu, who won the tournament 2021, lost in three sets 1-6 6-3 4-6 to her American opponent at Flushing Meadows, reducing her to tears after the encounter.
After being outplayed by Kenin in the opening set, the world number 72 responded in the second to take the match the distance in New York.
However, despite serving four of her six aces during the contest in the final set, Kenin would prove too strong to secure an all-American encounter with Jessica Pegula in the round of 64.
"I feel down, I feel sad," an emotional Raducanu said. "Obviously, this is a tournament I really want to do well in.
"I was maybe a bit slow starting. I would have preferred to probably play, a little bit more before coming into the US Open."
"You know, I know when I have a lot of matches, just like every player, you feel really good. You feel like everything's automatic.
"So yeah, I think I can learn from it. And you know my manage my schedule slightly differently."
Data Debrief: Raducanu loses the battle of former grand slam winners
Raducanu's match against Kenin is the second R128 match at this year's US Open between two former women’s singles grand slam winners.
And while not at her best, Kenin was able to showcase her resilience that won her the Australian Open in 2020, saving six of the nine break points she faced.
The top seed, who is aiming to progress beyond the quarter-finals at SW19 for the first time, prevailed 6-3 6-4 in the battle of the Grand Slam champions after 79 minutes on No.1 Court.
Swiatek had won the two previous meetings between the players - both of which came in major events, at the 2020 French Open final and this year's Australian Open.
The four-time Roland-Garros winner made a statement of intent, breaking her opponent twice in her opponent's first two service games on the way to taking the opening set.
Former Australian Open champion Kenin, who stunned Coco Gauff in the first round 12 months ago, looked to respond and forced a break-point opportunity at 4-3 down in the second set.
However, the American saw it go begging as she sent a forehand into the net, and the set remained on serve as Swiatek set up a second-round clash with Croatia's Petra Martic.
"On this surface, it's not about the result for me, about the progress," the Pole said in her on-court interview. "I'm just trying to be better every day.
"It was a solid start and not an easy draw, so I'm happy that I have a chance to play another match here. It's not easy to play a Grand Slam champion in the first round, so we have to be ready for everything.
"Obviously, I had a great beginning of the season, so I feel like I can come here and not worry about points or anything, and just focus on what I want to focus on. These are experienced players, so there’s no time to get into the tournament."
Data Debrief: Super Swiatek matches Henin and Radwanska
Swiatek arrived at Wimbledon with five titles to her name already this season, including three on the spin in Madrid, Rome and the French Open.
The world number one has now won each of her last 20 matches, achieving that feat for the second time in her career. Justine Henin in 2005 was the last player to register multiple streaks of 20+ WTA match wins before turning 24.
Notching her fifth straight win against a former major champion, Swiatek has now registered 72 Grand Slam singles wins, more than any other woman since the turn of the century.
She is also only the second player in the Open Era to win in the opening round of all the first 18 major events in a single decade, after compatriot Agnieszka Radwanska did so in the 2010s.
