With Ronaldo's early penalty having been cancelled out by Vytautas Andriuskevicius before half-time, Setkus was guilty of a blooper when he fumbled a strike from the Juventus forward to again hand this year's Nations League winners the advantage.
Ronaldo soon added two more before William Carvalho added a late fifth to seal the win over Group B's bottom side.
Second-placed Portugal moved within five points of leaders Ukraine, who they have a game in hand on, with the victory.
#EURO2020 Le point 🧐 après six journées 🔢— UEFA EURO 2020 🇫🇷 (@EURO2020) September 10, 2019
• Le top 2 de chaque groupe qualifié direct
• Les 4 autres qualifiés le seront grâce aux barrages établis à partir des résultats de la #NationsLeague 2018/19.
Ça va se tendre à partir d'octobre... 😋 pic.twitter.com/Ge3EsCvpgr
The visitors got off to the perfect start when they were handed a seventh-minute penalty after Markus Palionis was penalised for blocking Joao Felix's cross with his hand.
Ronaldo made no mistake as he kept his cool from the penalty spot, firing low into the bottom-right corner to add to the goal he scored in Saturday's win over Serbia.
Portugal continued to look a threat and Jose Fonte and Ronaldo both saw efforts saved by Setkus.
And the reigning European champions were left rueing those missed chances in the 28th minute when Andriuskevicius rose highest to head Mantas Kuklys' outswinging corner in off the post.
Then, somewhat inevitably, it fell to Ronaldo to turn the match back in Portugal's favour once more - but he had more than a helping hand from Lithuania goalkeeper Setkus.
What appeared a routine strike from Ronaldo from the edge of the area with 61 minutes on the clock was fumbled by the goalkeeper before spinning up and bouncing in off his back.
Ronaldo then made certain of the points four minutes later when he swept home Bernardo Silva's right-wing delivery before the pair combined again in the 76th minute, with the ex-Real Madrid player finding the bottom-right corner from inside the box.
Carvalho added further gloss in added time with a smart finish after the ball fell kindly to him inside the penalty area.
What does it mean? Portugal have fate in own hands but still have work to do
They might be the reigning champions and winners of the Nations League but Portugal still have work to do to seal automatic qualification.
This win keeps them second but leaders Ukraine remain in charge of the group and Serbia, in third, trail them by just a point.
Ronaldo still the man
It should come as no real surprise. Another season ticks by and, even now at 34, still Ronaldo continues to be the man for club and country.
Joao Felix might be the heir apparent but Ronaldo remains the one who makes Portugal tick.
Sympathy for Setkus
The Lithuania goalkeeper is unlikely to make a bigger blunder in his career. It was just unfortunate it came on the international stage.
He should not, however, be the scapegoat for what, in all likelihood, was an inevitable loss anyway - and the score would have been even higher but for a string of saves he made.
Portugal face Luxembourg in what will be viewed as another must-win match, while group leaders Ukraine - who also face the Euro 2016 winners in October - await Lithuania.