The victory ensures Portugal remain a point behind group leaders Serbia, who moved onto 17 points with a 3-1 home win over Azerbaijan, and boast a game in hand as well as superior goal difference with two rounds of matches remaining.
The treble, which meant Ronaldo became the first man to net 10 international hat-tricks, takes his tally to 115 international goals from 182 caps as he continues to extend his lead as the top men's international goalscorer of all-time.
Portugal had the game all but won within the opening 18 minutes as they raced to a three-goal lead. Ronaldo struck twice from the penalty spot in the 8th and 13th minutes: the first was awarded for a foul on Bernardo Silva by Sebastian Thill, though replays appeared to show the contact came outside the box.
For the second penalty, Ronaldo was fouled by goalkeeper Anthony Moris and after converting, he was forced to take it a second time as Andre Silva was judged to be encroaching in the area.
Five minutes later, Ronaldo's Manchester United teammate, Bruno Fernandes, made it 3-0 as he fired in following good work from Bernardo Silva. Midfielder Joao Palhinha added a fourth with just over 20 minutes to go, converting from a corner after Ronaldo's overhead kick effort was saved, before Ronaldo netted his 10th treble for his country -- and his first in over two years -- just three minutes from time with a header from close range, assisted by Ruben Neves.
Said Portugal manager Fernando Santos after the match, "we've achieved our first aim, which was to win this game. Now we have two more qualifiers left. We managed to restrain our rivals and take advantage of every situation to transform them into goalscoring opportunities."
Fernandes, who scored Portugal's third goal of the evening, was full of praise for his side's performance. "Scoring always helps regardless of whether it's early or not. We knew that Luxembourg, as time went by, would close themselves back and we had to start strong. That's what we did.
"I think we had a complete game overall and the most important thing was the result."
In the November window, Santos's Portugal side travel to Ireland before then hosting Serbia in what could be a winner-takes-all fixture to qualify for the 2022 World Cup in Qatar.