The Ireland lock, who captained the Lions on their tour of South Africa in 2009, sustained a hamstring injury during Sunday's victory over France, which now looks to be his final match on the international stage.
O'Connell also visited New Zealand in 2005 and Australia two years ago with the Lions, while he has amassed 108 caps for his country.
The 35-year-old, who joins European champions Toulon this season, will be sorely missed and fellow three-time Lion Ronan O'Gara took to Twitter to sing his praises.
He wrote: "My sadness is tinged with absolute pride having spent 16 years with one of Rugby's greatest competitors #gentleman #Leader #1ofakind"
Brian O'Driscoll added: "This is so wrong on many levels. One of the greatest leaders & players of them all. Inspirational."
Ireland Women's captain Niamh Briggs also shared her thoughts: "You always want to finish on your own terms but sport can be cruel!! True leader & inspiration...hope he gets back to play in France #iconic"
And the Munster Rugby Supporters Club tweeted: "Paul O'Connell has played his last game for Ireland.. A leader, a legend and a gent. All we can say is #ThanksPaulie"
Fans are now able to guarantee their place on the 2017 Tour to New Zealand with a fully refundable £250 Priority Access Pass for the official supporter packages. Guarantee your place at the front of the queue when ticket-inclusive travel packages go on sale during the 2015/16 season, and also receive an exclusive invite to meet the Lions Head Coach before they depart for New Zealand. With exclusive access to special events, flights and hotels, it's the genuine Lions experience - click here for more details.