Ferrero, the 2003 French Open winner who had to qualify for the event, beat Australian Open champion Safin 4-6 6-4 6-2 in an ill-tempered second round tussle at the Rothenbaum to show he will be a threat at Roland Garros in 12 days' time.
Top seed Federer enjoyed a 6-2 6-1 victory over Tomas Berdych, the 19-year-old Czech who inflicted one of the most painful defeats of the Swiss player's career at last year's Athens Olympics.
Ferrero has slumped to 39 in the rankings due to various fitness problems but the 25-year-old remains one of the world's finest players on clay and he had too much guile for the temperamental Safin on centre court.
The Russian won the first set after Ferrero double-faulted fatally at 4-5, 30-40. But he lost his cool at 2-0 down in the second set after an overruled line call and Ferrero, who beat Safin at last month's Monte Carlo Masters, took full advantage.
The Spaniard sealed the second set with a superb drop shot and ran away with the decider to set up a last 16 meeting with another Russian, Nikolay Davydenko.
An upset Safin later accused Ferrero of acting like a 14-year-old for intervening in his lengthy second-set dispute with the umpire but the resurgent Spaniard shrugged off the incident and said: "I feel I can beat anybody."
Defending champion Federer broke 19-year-old Berdych's serve in the opening game of each set and sealed a 53-minute victory with a decisive backhand volley on his first match point. It was his 37th win in 39 matches this year.
"He ruined my Olympic dreams in Athens so it's nice to get him back," said Federer. "Especially 6-2 6-1, that's a nice scoreline."
HENMAN GRUMBLES
The Wimbledon and U.S Open champion next faces Spain's Tommy Robredo who coasted to a 6-3 6-0 victory over Brazil's three-time former French Open champion Gustavo Kuerten.
Lying in wait for Federer as a potential quarter-final opponent is Argentine Guillermo Coria, the runner-up in last week's Rome Masters and at the 2004 French Open.
The 10th seed sped through to the third round by beating Russian Mikhail Youzhny 6-2 6-3.
Tim Henman won his all-British duel with Greg Rusedski 7-6 6-4 on court one in the first meeting between the two on clay.
The fifth seed was critical of the wet court conditions, saying: "It was very, very difficult. I don't know if I've ever played in tougher conditions."
French Open champion Gaston Gaudio, the fourth seed, beat former Roland Garros champion Albert Costa 7-5 6-0 while French 18-year-old Richard Gasquet, who upset Federer in Monte Carlo last month, defeated Olympic champion Nicolas Massu of Chile 2-6 6-2 6-2.
Italian qualifier Andreas Seppi also continued his fine run, knocking out Argentine 12th seed Guillermo Canas 7-6 6-2.
