O'Brien – known as 'The Tullow Tank' for his bullocking runs – makes his latest comeback for Ireland against Argentina at Lansdowne Road on Saturday.
It is almost a year since the 31-year-old farmer – a star for the British and Irish Lions in their 1-1 series draw with world champions New Zealand in 2017 –pulled on the green jersey, coincidentally against the same opponents.
Hip and shoulder injuries left him kicking his heels as the Irish secured the Six Nations Grand Slam and then a 2-1 Test series win in Australia.
However, his former Leinster team-mate O'Driscoll, while acknowledging the back row has a deep well of talent for head coach Joe Schmidt to call upon, says O'Brien is the one player would select in a crucial match.
"Dan Leavy's been great last season, Josh (van der Flier) has been excellent this year and Jordi Murphy's done nothing wrong," commented O'Driscoll, speaking at a media event organised by Guinness in Dublin.
"But when everyone's fit I still like Sean O'Brien as my openside starting for a World Cup quarter-final against whoever it might be.
"He's rated, he's got respect from those he's played with and against."
- 'No backward step' -
O'Driscoll, who under Schmidt at Leinster won two European Cups alongside O'Brien, said the flanker is someone who leads from the front.
"He's a real leader, you can hear his voice on every ref cam, every scrum, every ruck, he is literally barking away," said O'Driscoll.
"He's a Duracell bunny, he just does not stop. That brings a confidence. When someone's able to verbalise for 80 minutes, you know they're fit.
"The first thing that goes is the chat. I think he's a terrific player."
O'Driscoll, Ireland's record try scorer with 46 in 133 appearances, says that seeing O'Brien's name on the team sheet gives a confidence boost because of his combative qualities.
"There's some intangibles with Seanie, I think the confidence he brings when you see his name on the team sheet," said O'Driscoll.
"His experience, having done it before and delivered, there's not too many bad games that Sean's ever had.
"He is so confrontational and so aggressive that there's no backward step with him."
O'Driscoll, who experienced the joys of a Six Nations Grand Slam with the 2009 team, says that O'Brien is not just a wrecking ball breaking up opponents plays.
"It's comforting seeing that with one of your leaders, one of your leading ball-carriers, a guy that's destructive but also has really developed his skill-set," said the 39-year-old former centre.
O'Driscoll, who has forged a successful career as a pundit since retiring, admits O'Brien does not only deal roughly with opponents.
"He's the sort of player that if you rub up the wrong way he could do serious damage to you in training," he said.
"Those sorts of players are always frightening to have in your environment, but you're so thankful that they're on your side. And I think that says it all."