His exit reduces the Australian contingent to three with Alex de Minaur and Jordan Thompson still to play.
Popyrin had to work hard, losing the first set to Corentin Moutet, before dispatching the Frenchman 3-6 7-5 6-2 in two hours, 42 minutes. He will now face defending champion Andrey Rublev who had a first round bye.
O'Connell beat Aleksandar Vukic in Sunday's final qualifying round, a match that went to a third set tie-break, and 24 hours later was no match for Chile's Alejandro Tabilo, beaten 6-3 6-4 in 97 minutes.
De Minaur opens play on the red clay of Court Rainier III, the show court, on Tuesday (2210 AEST) against former grand slam champ Stan Wawrinka. Like Popyrin the Aussie No.1 has yet to get reach the last 16 in the event in three previous attempts, winning two of five matches.
Later in the day Thompson faces local favourite Gael Monfils, who at 37 is having a revival, breaking back into the world's top 50. The winner meets No.4 seed Daniil Medvedev.
Elsewhere on Monday two-time champion Stefanos Tsitsipas advanced after Laslo Djere of Serbia retired with an injury during the second set with the 12th-seeded Tsitsipas leading 6-3 3-2.
Ninth-seeded Grigor Dimitrov had little trouble beating local player Valentin Vacherot of Monaco, targeting his opponent's weaker backhand in a 7-5 6-2 win. The 32-year-old Bulgarian, a finalist in Miami recently, is chasing his second title of the year.
Dimitrov next plays either Matteo Berrettini — who on Sunday won the Grand Prix Hassan II in Morocco — or Miomir Kecmanovic.
Canada's Felix Auger-Aliassime had six aces and didn't concede a break point in beating Italian qualifier Luca Nardi 6-2 6-3, although things might get tougher in the second round against third-seeded Carlos Alcaraz.
However, Auger-Aliassime holds a 3-2 career record against the Wimbledon champion and two-time grand slam winner. Furthermore, Alcaraz has been practising with strapping to his right forearm.
Wtih record 11-time Monte Carlo champion Rafael Nadal out with an injury, second-ranked Jannik Sinner is the player to beat while No.1 seed Novak Djokovic is looking to win for the third time, but first since 2015.
With AP
