The 38-year-old superstar extended his already impressive tally of international goals to an astonishing 122 in 198 appearances.
The new coach, Roberto Martinez, made a smart move by restoring Ronaldo to the starting lineup, and it paid off well for the team.
Joao Felix, Bernando Silva, Otavio, and Rafael Leao also added to the scoreline, putting Portugal comfortably on top of Group J after an impressive start to their qualifying campaign.
Portugal took control of the game early on, with Ronaldo opening the scoring just nine minutes in, tapping in Nuno Mendes's header.
Joao Felix quickly followed up with another goal, heading Silva's cross to double the lead.
Silva then got his own name on the score sheet, heading in Joao Palhinha's cross, before Ronaldo added his second with a perfectly placed finish off a brilliant ball from Bruno Fernandes.
Luxembourg offered more resistance in the second half, but Portugal's substitutes proved to be just as lethal.
Otavio scored with a powerful header from Rafael Leao's looping cross, while Leao himself made it 6-0 with a stunning solo effort.
Despite missing a penalty kick, Leao redeemed himself by scoring the final goal, running half the length of the field to complete the impressive victory for Portugal.
With Ronaldo in top form and the team playing with confidence, Portugal looks like a formidable opponent as they continue their quest to qualify for Euro 2024.