Portugal manager Fernando Santos made four changes to the side that threw away a two-goal lead against Serbia on Saturday. Nuno Mendes, Renato Sanches, Ruben Neves and Joao Felix were all handed starts in place of Cedric Soares, Bruno Fernandes, Sergio Oliveira and Danilo Pereira.
The visitors dominated the early proceedings and forced Anthony Moris into some fine saves. However, Luxembourg were not fazed by the pedigree of their more illustrious opponents and pushed men forward on several occasions.
Their attacking impetus reaped dividends on the half-hour mark when Gerson Rodriguez placed home a glancing header from Daniel Sinani's cross to put the hosts one goal ahead.
The goal was Rodrigues' second of the qualifiers, having also scored the winning goal against the Republic of Ireland on Saturday.
Portugal were forced into a change when Joao Felix suffered an injury in the 40th minute and Pedro Neto came on in place of the Atletico Madrid forward.
Renato Sanches forced Moris into a superb save three minutes later. Just when it seemed like Luxembourg would hold on for a halftime lead, Diogo Jota levelled matters for Portugal with the last kick of the first half.
The Liverpool forward showed great awareness to latch onto a lofted pass by Neto and this brought his tally to three goals from two starts in this qualifying series.
A bright start to the second half saw Renato Sanches' goal-bound shot cleared off the line and this set the tone for what was to follow.
Portugal got the lead their bright start deserved six minutes after the restart. Ronaldo started and ended a brilliant counterattack that saw him convert Joao Cancelo's cross from the right flank.
The goal was Ronaldo's first in the current qualifying series and 103rd in the colors of Portugal.
Nuno Mendes forced Moris into yet another save less than a minute later and Diogo Jota hit the bar right on the hour mark.
Sebastian Thill was introduced 15 minutes into the second half and this saw him join his two brothers Olivier and Vincent on the field.
The hosts slowly regrew into the game and created some chances of their own, with Sebastian Thill drawing a fine save from Anthony Lopes with a free-kick from 20 yards.
Ronaldo was the beneficiary of a horrendous backpass that saw him come face-to-face with Moris but the Luxembourg goalkeeper produced two stunning saves from point-blank range to deny the Juventus man.
Portugal made sure of the result 10 minutes from time when Palhinha rose highest to head home a corner kick from Pedro Neto.
Maxime Chanot was shown his marching orders for two bookable offenses after a cynical challenge on Renato Sanches which saw the home side reduced to 10 men.
The victory sees Portugal climb to the top of Group A in UEFA's section of the 2022 FIFA World Cup Qualifiers, while Luxembourg remained in third place.
Here is how each Portugal player fared in the game.
Portugal Player Ratings
Anthony Lopes - 6.5/10
The Portugal goalkeeper was assured in his handling when called upon. Couldn't do anything about the opening goal but produced a fine save from a second-half freekick.
Nuno Mendes - 7/10
The Sporting Lisbon teenager continued to grow from strength to strength as he put up another assured display on the left flank of defense. He provided width in attack and got into good goalscoring positions which has probably seen him do enough to book his spot at the European Championship.
Ruben Dias - 6/10
Had a relatively sub-par game by his high standards. Was shown a second half yellow card for a cynical challenge.
Jose Fonte - 8/10
The 37-year-old is a favorite of Fernando Santos and he showed why with an immaculate display at the heart of defense. The Lille man made two crucial last-ditch interceptions when Luxembourg were in full flow in the first half.
Joao Cancelo - 8/10
It was another brilliant display from the Manchester City man. His bombarding runs forward were a constant source of worry for the hosts and he got a deserved assist six minutes into the second half.
Bernardo Silva - 7/10
Silva gave an assured performance as the creative link of his side. He made one key pass and had a passing accuracy of 97.3%.
Renato Sanches - 7.5/10
Renato Sanches was effective in his box-to-box role for Portugal and effortlessly linked defense with attack. Had a game-high passing accuracy of 98.5% but should have made more of the chances that fell his way.
Ruben Neves - 6.5/10
Neves was the weakest link in Portugal's midfield and did not offer much in an attacking sense.
Joao Felix - 4/10
Joao Felix was handed his first start of the qualifiers but he failed to make the most of his opportunities. The 21-year-old looked lost on several occasions and made some poor decisions before his injury-enforced substitution in the 40th minute.
Diogo Jota - 7.5/10
Diogo Jota seemingly has the Midas Touch at the moment and he was on the scoresheet yet again for Portugal. He also hit the bar from close range in the second half and received a booking before opening the scoring for his side.
Cristiano Ronaldo - 7.5/10
Ronaldo had several good chances to get a brace but failed to take any, while he also saw a goal ruled out for an offside decision. His goal means that he has now scored an international goal in every calendar year since he made his debut in 2004.
Pedro Neto - 8.5/10
Pedro Neto came on in the 40th minute and assisted the first goal six minutes later. He ended the night with two assists and was arguably man-of-the-match in what was just his 3rd appearance for his country.
Joao Palhinha - 7/10
The Sporting Lisbon man had just 22 minutes on the field but scored the crucial third goal that helped Portugal heave a sigh of relief. It was the perfect way to kickstart his Portugal career on what was his international debut.
Rafa Silva - 6/10
The Benfica man replaced Diogo Jota in the 68th minute and helped add an extra body in midfield.
Sergio Oliveira - N/A
Came on in the 90th minute and did not get enough minutes to warrant a rating.