With the Dragons dominating the Rabbitohs everywhere except the scoreboard in the first half, McGregor interchanged James Graham, Paul Vaughan and Jack de Belin simultaneously in the 27th minute.
Leeson Ah Mau, Jeremy Latimore and utility Kurt Mann, who played lock, were their replacements.
The starting trio were re-introduced gradually before the midway point of the second half to help the Dragons late in the match when the possession stakes inevitably shifted back towards their opponents.
"It was good coaching by Mary to put us all on at once because the game turned and we were defending our line but we had fresh bodies in the middle so it helped massively," Mann said.
"We had a lot of possession so he thought it would be good to get fresh bodies on there so we had a triple interchange. We ended up getting a try out of it just after half time and that period we went on we ended up doing a lot of defending so it worked well."
North Queensland coach Paul Green has used a similar ploy with great effect in recent seasons, with his two starting props and lock Jason Taumalolo usually coming to the bench around the 25th-minute mark and returning midway through the second half.
For McGregor to interchange Graham, Vaughan and de Belin at the same time indicates the confidence he has in the squad, which has been virtually unchanged during their five-game winning streak to start the season.
Every member of the starting line-up except Graham and hooker Cameron McInnes have scored tries so far this season in another sign of how well the Dragons are playing across the field.
The Cowboys rely on the tactic to steamroll teams at the back end of matches but the Dragons needed the refreshed Graham, Vaughan and de Belin to help them hang on against a Souths side who refused to give in.
"We wouldn't have won that game last year and in fact we didn't win that game against Souths last year, whereas we did this year, so that tells me we are going in the right direction," McGregor said.
"These games are what you can build your year on, we know we can play footy when we have got it but defensively we have kept another team under 16 points, which is our goal. It's as good as winning by 50, that's for sure."
After having just 31 percent of possession in the first half and not making it inside the Dragons 20m zone until the 35th minute, the Rabbitohs were predictably out on their feet by the end of the match.
However, it was a gutsy effort by Anthony Siebold's men to almost snatch an unlikely win after late tries by fullback Alex Johnston in the 72nd minute and Greg Inglis two minutes later.
For the opening 40 minutes it had been the Rabbitohs under siege. They were forced to make 124 tackles to 51 by the Dragons, who at one stage had 77 percent of possession.
The dominance of the home team in the first half was highlighted by how many metres Graham (100m), Vaughan (97m) and De Belin (94m) made in their 27-minute stints.
The Dragons had five more players who carried the ball further than 50 metres, whereas Dane Gagai was the only Rabbitohs player to do so.
However, the Dragons led just 8-2 at halftime and the final statistics show the extent of the second half turn around. By fulltime, the Dragons had made 302 tackles to 324 by Souths and both teams had completed 29 sets of possession.
As the Rabbitohs had done in the first half, the Dragons had to defend their tryline for long periods of the second half but they managed to hold on.
"The resilience we showed tonight and the pressure we were put under, it was a huge effort," Dragons captain Gareth Widdop said.
"You are not always going to win pretty all the time so these ones are important - the tough gritty wins when you have got your backs against the wall."