The Russian second seed was joined in the next round by a group of claycourt specialists, which included Spanish teenager Rafael Nadal and French Open winner Gaston Gaudio.
There was disappointment, however, for last year's winner, Carlos Moya, who was beaten 6-4, 7-6 by local wildcard Potito Starace.
The Spanish seventh seed was the highest ranking casualty of the tournament so far.
Moya retired from the semi-finals in Estoril last week with a shoulder injury and looked short of his best against Italian Starace.
"I came here to see if I could win a couple of matches and see how the shoulder was," Moya said. "If you have a look at the average speed of my service you'll realise there's something happening there.
"I tried and came close but you can't go far if you can't earn points on your serve," he added.
Accompanying Moya out of the tournament was the player he beat in the final last year, David Nalbandian, who let slip a final-set lead to lose 6-4, 1-6, 6-4 to Fabrice Santoro of France.
Safin, who has never progressed beyond the last 16 on the slow red clay in the Italian capital was plagued by lengthy lapses in concentration in the first set.
Having raced to a 4-1 lead, he committed a series of unforced errors allowing Czech Novak to break twice and serve for the set.
EARLY EXIT
Safin
Briefly it seemed Safin might be heading for an early exit but he closed out the second set in 26 minutes and then dominated the decider.
"I don't know what happened (in the first set)," said Safin, who next faces Spanish qualifier Nicolas Almagro.
"I think I was a little bit over-confident and tried to finish the first set too fast. I started to make some mistakes and lost my confidence."
If Safin is to win in Rome, he will probably have to beat 18-year-old Nadal on the way. The two are in the same half of the draw and, should the seedings work out, will meet in the quarter-finals.
Nadal has won four of the six claycourt tournaments he has taken part in this season, including last month's Monte Carlo Masters.
The fifth seed certainly made short shrift of 22-year-old Russian Mikhail Youzhny, who he beat 6-0, 6-2 inside an hour with a display of powerful and uninhibited hitting.
"I fell off a bit in the second set but I didn't feel the match was ever in danger of slipping away from me," Nadal said.
Argentine third seed Gaudio, winner of the Estoril Open, enjoyed an untroubled 6-4, 6-3 victory over Karol Beck of Slovakia.
It was a different story for Guillermo Coria, who needed almost three hours to battle past Fernando Gonzalez 7-6, 5-7, 6-4.