The 32-year-old debutant at the ATP's blue riband event won the first 11 games of the round-robin clash before a relieved Nishikori finally got on the scoreboard with an angled winner.
Normal service was quickly resumed though, as Anderson finished off a glum-faced opponent just past the hour mark.
Only six-times champion Roger Federer has enjoyed a 6-0 6-0 victory at the season-ending tournament, that coming in 2005 in Shanghai against unfortunate Argentine Gaston Gaudio.
Anderson, the first South African to qualify for the eight-man event since 1995, made it two wins from two round-robin matches with a stunning display.
What made it all the more impressive was that Nishikori had beaten Federer in straight sets on Sunday and that Anderson had trailed the Japanese 3-5 in their head-to-head record.
Another defeat for Federer would see the Swiss fail to reach the semi-finals for only the second time in his record 16 appearances at the tournament.
Anderson signalled his intent early and broke serve in the second game as Nishikori sent a backhand long under pressure.
The South African could do no wrong, dominating the baseline rallies and winning all but one of his 12 first service points as he took the opening set in faultless fashion.
He kept his foot on the accelerator in the second set and Nishikori, who qualified as a result of Juan Martin del Potro withdrawing with an injury, looked lost as the games ticked by and humiliation loomed.
When Anderson won the first point with Nishikori serving at 0-5 it looked ominous for the Japanese player. But he hit back to snatch a game at the death, earning sympathetic round of applause from the large afternoon crowd.
Despite this humbling defeat, Nishikori could still reach the semi-finals for a third time by beating Thiem in his final round-robin match on Thursday.
"I try to forget about today. Something was wrong. I've got to fix it tomorrow and try to be positive for the next one," the 28-year-old world number nine told reporters. (Reporting by Martyn Herman; Editing by Hugh Lawson)
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