But France only reduced the bleeding in the second half as England threw on reserves and rested stars such as Mako Vunipola, George Kruis, Ashton, and Sinckler in the third quarter.
Just as Ireland struggled against England with a makeshift full-back in Robbie Henshaw, France also - and perhaps strangely following last week's display - deployed an unfamiliar full-back in Yoann Huget to replace the injured Maxime Medard rather than use Thomas Ramos, who regularly plays in the position for Toulouse.
The irrepressible May bagged the first three and Henry Slade the fourth as England forged a remarkable 30-8 halftime lead.
England were not able to add to their tally until the 49th minute when they were awarded a penalty try after Ashton was illegally tackled by Gael Fickou with the France winger even sin-binned.
Barely had the anthems finished when France's bid for a first Six Nations win at Twickenham since 2005 was rocked by May's opening try.
"I'm Irish through and through but f*** me - Jonny May is on fire, fair play to England", one supporter said. "We work during the week and at the weekend we don't reap the rewards", the 30-year-old centre said.
Both Wales and England have won their opening two matches of this year's competition, with the possibility of acheiving the Grand Slam still within their grasp.
Osaka splits with coach Bajin Osaka, who withdrew from this week's Qatar Open due to a back injury, has not yet announced a replacement for Bajin. Osaka posted a tweet on Monday that says she "will no longer be working together with Sascha".
The home side thought they had opened the scoring in the fifth minute when full-back Sarah McKenna breezed past two opponents to touch down under the posts, but following an intervention from the TMO the try was ruled out after Poppy Leitch was penalised for blocking Menager in the scrum.
The second came with echoes of Jason Robinson as May stuttered and dummied to somehow create space from nothing to zip past Damian Penaud to score his second.
As the half hour mark was approaching England stepped up the accelerator with May diving over in the 24th minute and five minutes later May grabbed a grubber kick from Chris Ashton to complete a hat-trick as Eddie Jones' side stretched their lead to 23-3.
Jones added: "Jonny May's like when you go to the park and you see someone with a tennis ball and they throw it, the dog runs 100mph and chases it and brings it back".
England then showed terrific focus to defend their line and keep their shape amid the usual influx of replacements as France drifted to yet another defeat.
Jacques Brunel, the France coach, made six changes to his starting XV following that match but this humiliation meant his side had now lost 10 of their last 13 Tests.
"We never controlled the game in the first half", Guirado told ITV.