Quarter-final action at the $175,000 event was disrupted by rain a handful of times.
Williams had to wait out the completion of top seed and defending champion Patty Schnyder's win over ninth-seeded Sania Mirza of India, which was delayed twice, before she got on court in the final match of the evening.
Once she did, however, she made quick work of Frazier.
Williams, a seven-time Grand Slam champion, is competing for the first time since the Australian Open because of a nagging left knee injury.
The absence has seen her fall to 139th in the world rankings. But her return has been impressive.
Williams has not dropped a set and has lost just 12 games in three matches.
She'll face a tough semi-final match-up with unseeded Russian Vera Zvonarave, another former top 10 player who is playing her best tennis of the season.
Zvonareva trounced fifth-seeded Jelena Jankovic of Serbia and Montenegro, 6-1, 6-1 to to move into the semi-finals.
In the top half of the draw, Schnyder was pushed in a rain-delayed 7-6 (9-7), 7-5 victory over the 19-year-old Sania, who was playing in her first quarter-final this season.
After facing a match point in her first-round match, Schnyder has yet to lose a set as she looks to defend her 10th and most recent title.
Schnyder's semi-final foe will be fourth-seeded Katarina Srebotnik of Slovenia, who overwhelmed sixth-seeded Marion Bartoli of France 6-2, 6-1, to reach her first semi-final of the year.
Friday’s results:
Quarter-finals: Serena Williams (US) beat Amy Frazier (US) 6-2, 6-2; 1-Patty Schnyder (Switzerland) beat 9-Sania Mirza (India) 7-6 (9-7), 7-5; 4-Katarina Srebotnik (Slovenia) beat 6-Marion Bartoli (France) 6-2, 6-1; Vera Zvonareva (Russia) beat 5-Jelena Jankovic (Serbia & Montenegro) 6-1, 6-1.
US TRIO IN LAST FOUR
INDIANAPOLIS: Top seed James Blake completed a sweep of three Americans into the RCA Championships semi-finals with a 7-6, 7-6 win over Nicolas Mahut.
Blake joined compatriots Andy Roddick and Robby Ginepri in the last four, providing a boost for US tennis after a disappointing Wimbledon in which no American players survived the first week of the singles.
Blake landed a return winner on match point which required an electronic replay by the Hawkeye linecalling system before victory was confirmed.
Defending champion Ginepri and longtime rival Andy Roddick blasted into an Indianapolis meeting for a third straight year.
Ginepri dominated off-form Thai Paradorn Srichaphan 6-4, 6-1 while Roddick earned 6-2, 6-3 revenge against Gilles Muller.
Belgian ninth seed Xavier Malisse accounted for Chile's third-seeded Fernando Gonzalez 7-6, 6-4 to complete the semi-final lineup.
Results:
Quarter-finals: 1-James Blake (US) beat 10-Nicolas Mahut (France) 7-6 (7-2), 7-6 (7-5); 2-Andy Roddick (US) beat 12-Gilles Muller (Luxembourg) 6-2, 6-3; 4-Robby Ginepri (US) beat 8-Paradorn Srichaphan (Thailand) 6-4, 6-1; 9-Xavier Malisse (Belgium) beat 3-Fernando Gonzalez (Chile) 7-6 (7-4), 6-4.—Agencies