The 22-year-old Spaniard, who moved past Lucie Safarova on Monday, claimed a 6-4, 6-4 victory over her German opponent to go top of the White Group after both players had won their opening round-robin matches.
Venezuela-born Muguruza broke at 4-4 in the second set when Kerber sent a backhand pass wide before serving out for the set and putting one foot into the last four.
Muguruza has defeated Kerber several times this year, winning close encounters at the French Open, Wimbledon and at the Wuhan Open earlier this month.
She told wtatennis.com: “Every time I step on the court against Angelique I know it’s going to be difficult, so I just have to give my best if I’m going to get the victory.
“I’m really motivated to be here because it’s my first time in Singapore singles. So I really want to come here and win all the matches I can and, hopefully, go far.”
In the opening White Group match yesterday, two-times Wimbledon champion Petra Kvitova kept her hopes alive as she saw off Safarova in straight sets.
The 25-year-old fourth-seeded Czech defeated compatriot Safarova, who replaced defending champion Serena Williams – who withdrew to recover from a knee injury earlier this month, 7-5, 7-5 in an hour and 48 minutes.
Kvitova was beaten by Kerber in her opener on Monday but bounced back from a 3-0 deficit in the second set to come out on top in a tense finale against Safarova.
The 2011 winner was delighted to claim her first win and said: “I’m really glad that I was able to play and win the kind of match after my loss in the first match here.
“For sure, it was a difficult match. I know that Lucie wasn’t really healthy weeks ago and I’m just happy that she’s here as well.
“It’s great to have two Czechs in the WTA Finals.”
Meanwhile, British No 2 Aljaz Bedene was knocked out in the second round of the Valencia Open.
The 26-year-old, who was born in Slovenia but gained UK citizenship in March, fell to a 6-3, 6-4 defeat to Canada’s Vasek Pospisil. It was a disappointing afternoon for the world No 48, who had beaten French eighth seed Jeremy Chardy 3-6, 6-2, 6-1 in round one.Pospisil will play either German qualifier Daniel Brands or top seed David Ferrer of Spain in the next round.
Elsewhere America’s Steve Johnson continued his fine recent form with a 6-3, 6-4 win over Slovakian Martin Klizan.
Johnson up to a career-high ranking of 33 following his exploits in Vienna, where he lost to Ferrer in the final, set up a meeting with another Spaniard, Feliciano Lopez.
Uruguay’s Pablo Cuevas pulled off a shock by beating Australian third seed Bernard Tomic, Roberto Bautista-Agut won an all-Spanish clash against Nicolas Almagro and Russian Andrey Rublev swept past Marcel Granollers of Spain in straight sets.