Dan Cole and Ben Spencer also missed out on Jones' 34-man squad for the tournament, which England begin with an away clash against France on 3 February (AEDT).
The omission of versatile back Nowell was the biggest surprise of the 10 players from England's Rugby World Cup squad who are not selected, many of whom are injured - including Billy Vunipola (broken arm).
Capped 34 times by his country, the 26-year-old has played regularly for Exeter Chiefs despite struggling with his recovery from an ankle injury suffered prior to the World Cup and reports suggest he will now undergo a second operation.
Alex Moon, Fraser Dingwall and Jacob Umaga earn call-ups for the first time, along with George Furbank and Will Stuart.
Tom Dunn, Ben Earl and Ollie Thorley have been in previous squads and have another chance to make their England debuts.
Alex Mitchell and Josh Hodge are called up as apprentice players.
Seven Saracens players earned a selection after the news the European champions will be relegated from the Premiership at the end of the season.
The squad will meet at Pennyhill Park on Wednesday to begin their Six Nations preparation, before flying to Portugal a day later.
Jones said: "It is always about winning the next game so we have picked the best squad available.
"At the same time we wanted to bring some young players in because we need to keep building our depth so for those new players it is an exciting opportunity for them.
"The first three days will be about getting organised. We have got players from 11 clubs so we need to get everyone on the same page quickly and spend a lot of time working on our togetherness.
"Then by Tuesday next week we are in Test preparation for France."
Forwards: Luke Cowan-Dickie, Tom Curry, Tom Dunn, Ben Earl, Charlie Ewels, Ellis Genge, Jamie George, Ted Hill, Maro Itoje, George Kruis, Joe Launchbury, Courtney Lawes, Lewis Ludlam, Joe Marler, Alex Moon, Kyle Sinckler, Will Stuart, Sam Underhill, Mako Vunipola, Harry Williams.
Backs: Elliot Daly, Ollie Devoto, Fraser Dingwall, Owen Farrell (captain), George Ford, George Furbank, Willi Heinz, Jonathan Joseph, Jonny May, Ollie Thorley, Manu Tuilagi, Jacob Umaga, Anthony Watson, Ben Youngs.