Wasps wing Christian Wade will get his first taste of international rugby while fellow new faces Joe Launchbury, Alex Goode and Jonathan Joseph are likely to make their bows off the bench.
The majority of Lancaster's side remains unchanged though with 11 players who featured during the Six Nations also appearing against the Barbarians.
And the head coach, who is preparing to take charge of his first tour, insists his selection policy reflects his desire to maintain the momentum that took England to four victories in the spring.
"We are treating this as a very important game for setting the foundations for the tour," he said. "The players have been excellent this week and have been fully focussed as we are looking to build on the momentum of the Six Nations. This is a really important milestone in our preparation for South Africa.
"With the Leicester and Harlequins players unavailable it's a great opportunity for those other players involved in the Six Nations to lead the way.
"Some of the younger players have a chance to put a marker down and get their first taste of international rugby such as Christian Wade on the wing, Joe Launchbury, Alex Goode and Jonathan Joseph on the bench.
"Being able to name a back line very similar to the Six Nations and the strength we have in the forwards with the likes of Tom Johnson and Carl Fearns, who played in this game last year, is a real positive.
"The support we had at Twickenham against Wales and Ireland was fantastic and we can't wait to get back there. The Barbarians have a really strong team packed with talent and experience and having been involved in this fixture before I know it will be a great occasion."