Like a rabbit caught in the Centre Court floodlights, the world number 55 was given a tennis lesson by the Swiss maestro in a second-round mismatch.
Federer, who next meets 2002 runner-up David Nalbandian, was forced to wait around all day after the earlier two Centre Court matches went the distance and he was in no mood to waste any more time in his first ever match under the rainproof roof.
He raced into a 3-0 lead in the first two sets with the crowd taking increasing pity on the left-handed Frenchman, who had no logo on his inexpensive shirt and too often fired his serves into the net.
The ever-diplomatic Federer did not mind the crowd urging on the underdog.
"The atmosphere was fantastic," the third seed said.
"It's unusual, it's very nice to play indoors for the first time, I've played 10 years on Centre Court."
Such was the ease of the encounter that Federer began to drop his guard and a huge roar went up when Mannarino sent a superb a winning passing shot hurtling past the Swiss on his way to three break points.
Federer, though, simply cranked up the gears and stormed back to take the game and the second set before sealing victory to light applause, as if the crowd had become too accustomed to his beguiling brilliance.
They quickly fell in love with him again when streams of autograph hunters appeared at the end and Federer could well do with their support against tricky Argentine Nalbandian.
"I didn't enjoy playing against him too often," he said. "I expect it will be a difficult match."
Isner returned to Court 18, which now boasts a plaque to commemorate last year's record-shattering 11-hour epic win against Nicolas Mahut, but was beaten 7-6(3) 7-6(5) 6-7(5) 6-3.
Isner had beaten Mahut in a much-hyped rematch in the first round but was never able to make much impression against the hard-hitting 16th seed Almagro.
He served 28 aces but did not have a single break point on the Spaniard's serve. Almagro claimed the only break of the match early in the fourth set as he went on to seal a third round encounter with Russian Mikhail Youzhny, who beat India's Somdev Devvarman 6-2 6-4 6-4.