Fritz, ranked ninth in the world, reached his seventh tour-level semi-final of the season with his first career win in four meetings with Nishikori.
Nishikori was playing his first ATP event since 2021 as he returns from left hip surgery in January 2022. "I'm super happy how I played today, getting better and better each day I feel like," Fritz said in his post-match on-court interview.
"A lot of positives I can take into the next match. Kei has been around since I first started. He's an incredible player and a great guy.
"I'm just happy to see him back playing again, having good results and hitting the ball well after being injured for so long," added Fritz, who had lost three prior meetings with Nishikori but hadn't played him since 2019.
Nishikori, owner of 12 ATP titles and runner-up at the US Open in 2014, launched his comeback this season on the lower tier Challenger Tour, capturing the title at the Caribbean Open Challenger in Puerto Rico in June.
He arrived in Atlanta ranked 439th in the world and posted victories over Australian Jordan Thompson and China's Shang Juncheng to reach the quarter-finals.
But he and Fritz held serve with ease through the first five games, Fritz finally pouncing on the first break point of the match to pocket the first set after 34 minutes.
Nishikori, who appeared to be struggling somewhat with his movement around court, received treatment on his left knee during a medical time out between sets, and after dropping serve in the second game could never get back on terms.
Fritz, who is seeking a second title of the season after winning the fifth of his career at Delray Beach in February, will face eighth-seeded American J.J. Wolf for a place in the final.
Wolf beat Germany's Dominik Koepfer 6-2, 6-3. There was a blow to local favourite Christopher Eubanks who, after a two-hour rain delay, lost 6-4, 6-4 to Australia's Aleksandar Vukic.
The 27-year-old Vukic reaches an ATP Tour semi-final for the first time after punishing the unforced errors from Wimbledon quarter-finalist Eubanks, who was born in Atlanta.