The No.8 fractured his left arm in Sunday’s 13-3 Heineken Champions Cup win over Glasgow.
Vunipola broke his right arm twice last season, missing the final Test of England’s tour to South Africa, and has only played one full 80 minutes this season.
His elder brother, prop, Mako suffered a calf strain in Sunday’s game and is set for an undetermined spell out of the game as is forward Nick Isiekwe who sprained an ankle at the weekend.
Billy Vunipola’s absence is a massive blow for England head coach Jones ahead of autumn internationals against South Africa, New Zealand, Japan and Australia.
Exeter’s Sam Simmonds is already out of the equations with a gruesome knee injury and Wasps’ No.8 Nathan Hughes faces a ban.
Hughes is up before a disciplinary panel on Wednesday for punching in Wasps’ Premiership match against Gloucester the weekend before last.
His initial hearing was postponed when he tweeted ‘What a joke’ from the proceedings and he can expect to miss at least the first couple of autumn games.
Next in line for the No.8 spot are Bath youngster Zach Mercer or Newcastle’s versatile back rower Mark Wilson but it is a body blow for Jones.
Big Billy has only started two games for England since March 2017 against Ireland and has suffered shoulder, knee and arm injuries in the last couple of years.
His shoulder problems ruled him out of last year’s British & Irish Lions tour to New Zealand.
Mako Vunipola is similarly irreplaceable for England with Joe Marler retired and Ellis Genge and Matt Mullan injured along with Beno Obano of Bath.
Widely seen as the leading all-court loose-head in the world Mako’s potential absence opens up the way for Exeter’s Alec Hepburn or Gloucester’s Georgian born Val Rapava Ruskin.
Maro Itoje and Jamie George broke their noses in Sunday’s bloodbath but should be fit for this weekend’s round two game against Lyon at Allianz Park and wing David Strettle was another casualty.
Owen Farrell banged his knee in the same game but that is not thought to be too serious but it is for Jones who has to patch up his England side after this latest calamity.
The Australian is set to name his squad for the autumn at Twickenham on Thursday morning and also has doubts over wing Nathan Earle who limped out of Harlequins Challenge Cup win over Agen on Saturday.