Williams showed no ill effects after withdrawing from the Madrid Open and fired down seven aces as she progressed in one hour and 15 minutes.
One break was enough to secure the first set for the world number one and a further three followed in the next as Williams progressed to the third round with then minimum of fuss.
"I was really happy with my level," Williams told the WTA website after the match.
Williams wins first title in nine months in Rome
"I think I was really consistent. I think I was mentally consistent. I started out fast. Those are some of the things I wanted to work on [and] I was really happy about that."
Earlier, Johanna Konta was a 6-1 6-2 winner over Johanna Larsson of Sweden in the Italian Open first round.
The British number one threw down eight aces in joining fellow Brit Heather Watson in the second round in Rome.
Australian Open semi-finalist Konta - up to 23 in the world - will next meet Roberta Vinca of Italy.
The world No. 55 Watson beat Sara Errani 6-4 3-6 6-0 in two hours and 16 minutes and will face Czech Republic's Barbora Strycova in round two.
Results from the Italian Open
1-Serena Williams (U.S.) beat Anna-Lena Friedsam (Germany) 6-4 6-3
8-Carla Suarez Navarro (Spain) beat Teliana Pereira (Brazil) 6-1 7-5
9-Svetlana Kuznetsova (Russia) beat Caroline Garcia (France) 7-5 6-4
11-Timea Bacsinszky (Switzerland) beat Yanina Wickmayer (Belgium) 6-2 6-2
Lesia Tsurenko (Ukraine) beat Julia Goerges (Germany) 1-6 7-6(5) 6-3
Daria Gavrilova (Australia) beat Sabine Lisicki (Germany) 6-1 7-6(3)
Samantha Stosur (Australia) beat Alison Riske (U.S.) 4-6 7-6(5) 6-1
Christina McHale (U.S.) beat Claudia Giovine (Italy) 6-1 2-6 6-2
Eugenie Bouchard (Canada) beat Jelena Jankovic (Serbia) 6-4 2-6 6-3
Johanna Konta (Britain) beat Johanna Larsson (Sweden) 6-1 6-2
Jelena Ostapenko (Latvia) beat Kristina Mladenovic (France) 6-3 6-1
Timea Babos (Hungary) beat Kiki Bertens (Netherlands) 6-1 6-4
Mariana Duque (Colombia) beat Monica Niculescu (Romania) 6-4 6-1
Williams sets up all-American Rome final with Keys
Konta relishing clash with Rome favourite Vinci