The Serb was all smiles as he got the job done in his second-round start after a bye after losing a week ago in his opening match in Madrid to Grigor Dimitrov.
The Bulgarian threat was knocked out earlier by French ninth seed Richard Gasquet 6-4, 6-4.
Rafael Nadal began building for what he hopes will be a lucky seventh title at the Foro Italico after winning Madrid, his fifth title of a season which only began for him in February as he returned following seven months of knee injury absence.
"It's a little different here with the (lower) altitude. Playing three Masters 1000s (form Monte Carlo a month ago) is difficult when you are in the final rounds.
"There is no time to prepare the next tournament. I arrived on Monday and I'm here to try my best."
Djokovic wasted no time in his victory as he tries to finally rid himself of ankle problems which have bothered him for a month.
The top seed improved to 23-4 in Rome, where he won 2008 and 2011 titles.
In first-round play, Djokovic's fellow Serb Viktor Troicki spoiled the possibility of a Nadal rematch with Lukas Rosol as he beat the Czech 3-6, 6-1, 6-4.
Rosol upset Nadal in the Wimbledon second round before the Spaniard was forced off court for his knee recovery.
Frenchman Julien Benneteau defeated 12th seed Nicolas Almagro 7-6 (7/2), 6-4 while Russian Mikhail Youzhny surprised German number 13 Tommy Haas 6-4, 6-3.
The 35-year-old Haas won the Munich clay title little more than a week ago and reached the third round in Madrid.
Madrid finalist and 15th seed Stanislas Wawrinka staged a fightback to overcome Carlos Berlocq 5-7, 6-3, 6-3.
Spain's Fernando Verdasco beat Argentina's Horacio Zeballos in three sets, while Frenchman Jeremy Chardy also needed three sets before beating Spaniard Feliciano Lopez 3-6, 7-5, 7-6 (7/4).
Argentine seventh seed Juan Martin del Potro was making his return to action after a virus, taking on Russian Andrey Kuznetsov.
Among the women, Briton Laura Robson was no match for world number one Serena Williams, who advanced 6-2, 6-2 in their second round meeting - their first career encounter.
Robson beat the American's sister Venus in the previous round but was unable to pull off another surprise as Serena moved to a meeting with either Melanie Oudin or Dominika Cibulkova in round three.
Former world number one Caroline Wozniacki is still without a win in a major clay-court tournament this season as the French Open approaches after losing a marathon match to Bojana Jovanovski 2-6, 6-4, 7-6 (7/5).
With her victory, the 21-year-old from Belgrade ended a poor run of form and claimed her first win since mid-January at the Australian Open.
The 10th-seeded Wozniacki laboured for almost three hours in a struggle which ended in front of a standing-room only crowd as she lost to her 48th-ranked opponent in their first-round match. Watching was golfer boyfriend Rory McIlroy.
Russian Maria Kirilenko restored order for the seeds at the Foro Italico as the number 12 beat Spain's Anabel Medina Garrigues 6-3, 6-3. Meanwhile, German Julia Goerges advanced over Czech Andrea Hlavackova despite losing the opening set and Varvara Lepchenko of the US defeated Lesya Tsurenko 6-4, 6-2.
Ursula Radwanska of Poland upset 15th seed Ana Ivanovic 6-3, 2-6, 6-2.
2011 Wimbledon winner Petra Kvitova became the first woman into the third round, beating Germany's Sabine Lisicki 6-4, 0-6, 7-5.