It is the standout tie to come out of the draw, with six-time former winners Bayern Munich to play Spanish champions Atletico Madrid in the most notable another match-up, while leading English contenders Manchester City, Liverpool, and holders Chelsea were all handed opponents that they will expect to beat.
United and PSG will meet for the third time in four seasons with the French club at home in the first leg in February after coming second behind City in Group A.
That is despite signing the 34-year-old Ballon d’Or winner Messi from Barcelona in August, just before Ronaldo returned to Old Trafford for a second spell from Juventus.
Five of Messi’s six goals for PSG so far have come in the Champions League, while Ronaldo has 13 goals this season for United, with six in Europe.
Ronaldo will turn 37 in early February. He scored twice when Juventus beat Messi’s Barcelona 3-0 away in the group stage last season.
United famously beat PSG in the last 16 in 2018/19 at the start of Ole Gunnar Solskjaer’s reign as manager, recovering from a 2-0 loss at home in the first leg to win the return 3-1 and advance on away goals thanks to a late Marcus Rashford penalty.
The clubs also met in the group stage last season, with the away side winning on each occasion.
Pep Guardiola’s City will play Villarreal, who beat United on penalties in last season’s Europa League final and qualified for the last 16 ahead of Atalanta.
Premier League champions and current leaders City lost last season’s final in Porto to Chelsea, who were the only English team not to win their group.
That meant Thomas Tuchel’s team could have been drawn against Bayern or Real Madrid, so they will be relieved to be facing French champions Lille, who topped their own section but are currently in mid-table in Ligue 1 and are in the knockout phase of the Champions League for the first time since 2006/07.
Meanwhile, Liverpool, who have lifted the trophy six times, will play Austrian champions Red Bull Salzburg, a team through to the knockout phase for the first time.
Jurgen Klopp’s side beat Salzburg twice in the group stage in 2019/20, winning 4-3 at Anfield and then 2-0 away. Chelsea also won home and away against Lille in that season’s group phase.
Record 13-time European champions Real Madrid were drawn against two-time former European Cup winners Benfica, with the first leg in Lisbon.
Inter Milan play Ajax and Portuguese champions Sporting will take on Juventus. They will hope to emulate their compatriots Porto, who knocked out the Italian giants at the same stage last season.
The first legs will be played in the second half of February with the second legs in early March.
This season’s Champions League final will be played in the Russian city of Saint Petersburg on May 28.