Hoffman, who had stepped on the podium on three previous occasions at the annual race, broke clear of the bunch to win a sprint finish in 2:39:31.
Meron Teshome Hagos of Eritrea, whose MTN Qhubeka Feeder team had done most of the hard work in the latter stages of the 109km race, held on to finish second, with HB Kruger of Team Bonitas taking third place.
Hoffman, riding for Team Abantu, had finished fifth in the 15km scratch race at the UCI Track World Championships in Cali, Colombia, last month and used his speed to open a two metre gap on the peloton by the time he crossed the line.
"There was sort of chaos among the MTN boys and that fell into my hands because they had the numbers," Hoffman said.
"They pretty much controlled it, which was perfect for me. I can hold myself in a sprint and I can see which wheels to follow.
"Knowing there weren't any strong guys, I had the confidence to sprint against these guys, but it wasn't easy."
Stander, who last won the women's event in 2011, took the early lead and controlled the race from the start.
While seven-time winner Anriette Schoeman was lurking in the closing stages, she lost some ground on the climbs approaching the finish.
Stander, surrounded by a group of men in windy conditions, managed to avoid a crash when one of the male riders in front of her fell just before the line, and she maintained her momentum to win the women's title in 2:51:00.
Schoeman was second in 2:51:31, with veteran Dee Joubert taking third position in 2:53:03.
Stander, riding for the RECM team, was pleased to be back to her best after struggling last year following the deaths of her husband Burry Stander, and her grandmother.
"My gran was the anchor in my cycling career.
"She supported me since I was nine years old," Stander said.
"Over Suikerbossie (hill) I just kept thinking about her and Burry, and how much I wanted this win for both of them.
"I'm extremely happy and they were the motivation that got me over the line."
Results of the Cape Argus Pick n Pay Cycle Tour in Cape Town on Sunday:
1 Nolan Hoffman (RSA) 2:39:31, 2 Meron Teshome Hagos (ERI) same time, 3 HB Kruger (RSA) st, 4 Nicholas Dougall (RSA) st, 5 Fran Rabon (CZE) st, 6 Jayde Julius (RSA) st, 7 Shaun-Nick Bester (RSA) st, 8 Karl Platt (GER) st, 9 Darren Lill (RSA) st, 10 Costa Seibeb (NAM) st
1 Cherise Stander (RSA) 2:51:00, 2 Anriette Schoeman (RSA) 2:51:31, 3 Dee Joubert (RSA) 2:53:03