Matthew Rees and Adam Jones, both second-half replacements in Durban, come in for Lee Mears and Phil Vickery in the front row, while Simon Shaw replaces Alun-Wyn Jones at lock.
Luke Fitzgerald takes over from Ugo Monye on the left wing, with fellow Leinster and Ireland star Rob Kearney starting at full back after replacing Lee Byrne after 38 minutes at the ABSA Stadium.
"The changes are just to try and have a balance to what we want to do knowing that it could be a very different game at the weekend," explained McGeechan.
"We've tried to pick on form and on what we've seen. Luke Fitzgerald played well again on Tuesday and Rob Kearney played very well when he came on at the weekend. That familiarity will hopefully stand us in good stead.
"We have made five changes to the starting XV but it will not change the way we want to play. Both teams will be better for the run last weekend and we know we will have to step up our performance to ensure that we again take the game to the opposition and are more accurate in taking our opportunities."
The Lions trailed by 19 points with just 12 minutes of the first Test remaining before hitting back to fall just short in an extraordinary finale. McGeechan believes there were plenty of positives to be taken from that opening encounter but he has made it clear to his players that Saturday's clash at Loftus Versfeld in Pretoria is an entirely new ball game.
"It will be a different Test match, different conditions," added McGeechan.
"There were many positives to come out of the First Test which we have built upon this week but you've just got to look at starting again. That one is finished, done and dusted. This will be a new challenge and a new game completely.
"You can't say what is going to happen. What you try and do is get your own game right so that you can be competitive, getting our execution and everything else as effective as it can be so that we become a threat and a challenge and produce a game then that is difficult for South Africa to play against.
"As a squad the Lions still have everything to play for. The players know that the outcome of the Test series comes down to Saturday and they are determined to take the series to a decider in Johannesburg."