Cipriani, who started England's victory over South Africa last time out, was named as the Premiership's player of the month for September, but is left out in favour of Farrell, Leicester's George Ford and Saracens utility back Alex Lozowski.
Wing Chris Ashton returned despite yet having to make his debut for new club Sale with his seven-week ban for a tip-tackle elapsing this weekend.
With Joe Marler retired from worldwide duty and Ellis Genge, Matt Mullan and Beno Obano all injured, Jones will most likely have to hand a debut to Ben Moon or Val Rapava Ruskin, or a first start to Alec Hepburn against the Springboks.
"It gives an opportunity for some good new players to play some important Tests for England, while players who have been in the squad before will have to take on more responsibility".
With brother Billy among 15 other frontline players missing Eddie Jones's plans for England's November series are in turmoil and his options at loosehead prop particularly bleak. "We can only control what we can control and injuries have happened", said Jones.
Forwards (20) - Tom Curry (Sale Sharks), Charlie Ewels (Bath Rugby), Jamie George (Saracens), Dylan Hartley (co-captain, Northampton Saints), Alec Hepburn (Exeter Chiefs), Ted Hill (Worcester Warriors), Maro Itoje (Saracens), George Kruis (Saracens), Courtney Lawes (Northampton Saints), Zach Mercer (Bath Rugby), Ben Moon (Exeter Chiefs), Ben Morgan (Gloucester Rugby), Michael Rhodes (Saracens), Nick Schonert (Worcester Warriors), Brad Shields (Wasps), Kyle Sinckler (Harlequins) Elliott Stooke (Bath Rugby), Sam Underhill (Bath Rugby), Harry Williams (Exeter Chiefs), Mark Wilson (Newcastle Falcons).
Tigers centre Tuilagi is joined by George Ford, Jonny May and Ben Youngs in the selection made by England head coach Eddie Jones.