Chris Robshaw has been confirmed as captain of a squad that also features the return of James Haskell as well as Care.
Care was excluded from England's Six Nations campaign on disciplinary grounds while Haskell was unavailable because he was playing in the southern hemisphere.
The inclusion of Leicester's Tom Youngs as one of four hookers is the most left-field selection, given he has never started a Premiership match in that position.
The converted centre has made 12 bench appearances for Leicester and will compete with first choice Dylan Hartley, Lee Mears and the uncapped Harlequin Joe Gray for the hooker's jersey.
Youngs will join his scrum-half brother Ben in the senior England squad for the first time and he is joined by Tigers team-mate Graham Kitchener as a fellow England newcomer.
The Wasps pair of wing Christian Wade and flanker Joe Launchbury have been rewarded for their excellent Premiership seasons in a struggling side with a first senior call-up.
Lancaster has drafted in Bath flanker Carl Fearns and Exeter loose forward Tom Johnson after losing Tom Croft and Tom Wood to injury and Callum Clark to suspension.
Despite England's back row selection issues, there is no return for Nick Easter or Toulon's Steffon Armitage, but Haskell is picked ahead of his return to Wasps from the Otago Highlanders next season.
Harlequins, who finished top of the regular season Premiership table and face Northampton at home in Saturday's semi-final, also provide lock George Robson and centre George Lowe.
Saracens full-back Alex Goode and London Irish centre Jonathan Joseph also win their first senior England call-ups
Care and Haskell are not the only returnees. Harlequins wing Ugo Monye, Worcester prop Matt Mullan and Leicester centre Anthony Allen are all back involved in the senior England squad.
Monye won his last England cap in the 2010 Six Nations, the same championship in which Mullan made his only Test appearance, off the bench against Italy.
Allen won his two England caps in 2006 when Andy Robinson was coach.
England have never embarked on a three-Test tour of South Africa before and they have two midweek matches against teams select XVs drawn from the domestic Currie Cup competition.
Lancaster said: "There is a real excitement about this squad. We have a massive challenge ahead of us but it is one that everybody involved, players, coaches and management, is looking forward to.
"Chris Robshaw was named player of the season on Tuesday night so congratulations to him and it is only right that he continues to captain the team, supported by a strong leadership group.
"While certain players are not available because of inevitable injuries at this time of the season, we have been able to select the bulk of the squad from the RBS 6 Nations.
"We are also taking with us four of the Under-20s team which reached last June's Junior World Championship final (Owen Farrell, Joseph, Launchbury and Wade) and we see the return of two experienced internationals in Danny Care and James Haskell."
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