The second-seeded four-time runner-up Federer whipped Frenchman Jeremy Chardy 6-2, 6-1, while the third-seeded eight-time champion Nadal won by an identical 6-2, 6-1 score against a Frenchman of his own, Lucas Pouille, at the famed Monte Carlo Country Club.
Federer lost to Stan Wawrinka in a rare all-Swiss final last year in Monte Carlo, as he is still seeking an elusive title here.
The "King of Clay" Nadal won an Open Era-record eight consecutive titles at this event from 2005-2012 and has a brilliant 51-3 record in the storied tournament.
Federer's third-round opponent on Thursday will be xxxx, while Nadal will encounter 15th-seeded towering American John Isner.
Meanwhile, fourth-seeded Canadian slugger Milos Raonic defeated Portuguese Joao Sousa 6-3, 7-6 (7-4), sixth-seeded Czech Tomas Berdych handled Ukrainian Sergiy Stakhovsky 6-4, 7-6 (7-2) and a seventh-seeded Wawrinka opened defense of his lone Masters title by dismissing Argentine Juan Monaco 6-1, 6-4 on Day 4.
Ninth-seeded Bulgarian Grigor Dimitrov spanked Italian Fabio Fognini 6-3, 6-4, while 10th-seeded Frenchman Gilles Simon bested fellow countryman Benoit Paire 6-4, 7-5 and 11th-seeded Frenchman Jo-Wilfried Tsonga took care of quality Belgian David Goffin 6-3, 6-4.
Also on Wednesday, 12th-seeded Spaniard Roberto Bautista Agut overcame German Philipp Kohlschreiber 6-7 (3-7), 6-3, 7-6 (7-4), the 6-foot-10 Isner topped Serb Viktor Troicki 7-6 (7-4), 7-6 (7-5) and 16th-seeded Tommy Robredo drilled fellow Spaniard Marcel Granollers 6-1, 6-1 at the first clay-court Masters event of the season.