Nacer Chadli and Kevin De Buryne also got on the scoresheet as Marc Wilmots' men began their World Cup preparations in comfortable style.
Chelsea striker Lukaku will play a key role at the upcoming World Cup for coach Marc Wilmots after fellow forward Christian Benteke was ruled out with a serious Achilles injury.
And he warmed up for the Brazil showpiece in style, as his well-taken treble highlighted Monday's routine win in Genk.
Januzaj's appearance was also noteworthy, with the Manchester United youngster – the subject of lengthy debate about his international future – coming off the bench at half-time.
Another substitute, Tottenham's Nacer Chadli, scored the fourth before Kevin De Bruyne netted a late penalty as Belgium, eventually, won well.
This was by no means a vintage performance, though, and Wilmots will demand more from his side in further pre-World Cup friendlies against Sweden and Tunisia.
Goalkeeper Simon Mignolet sustained a minor injury in training Saturday and Atletico Madrid's Thibaut Courtois was rested after featuring in the weekend's Champions League final.
With Hoffenheim's Koen Casteels also injured, 28-year-old shot-stopper Sammy Bossut – who plays his club football for Zulte-Waregem – made his international debut.
Lukaku gave Belgium the lead in just the third minute after Marouane Fellaini dispossessed Lars Gerson and played in the striker, who shot around advancing Luxembourg goalkeeper Anthony Moris and in.
Aurelien Joachim scored a stunning equalizer for Luxembourg just 10 minutes later, though, beating Bossut with an outstanding 30-yard strike.
Joachim held off the attentions of Thomas Vermaelen to take down a long ball, before lashing in with his left foot, and the same player caught Vincent Kompany napping in the 17th minute, only for Bossut to deny him with an impressive save.
Fellaini headed a corner over before Lukaku got his second with 23 minutes gone, as he pounced after Maxime Chanot's attempted clearance fell into his path, and scored, via a ricochet off Moris.
Lukaku lifted over Moris – but wide – and his search for a third went on as the goalkeeper saved superbly to his right three minutes before the break.
Januzaj was one of Wilmots' five halftime changes and saw Lukaku become the first player to score a hat-trick for Belgium since Bob Peeters achieved the feat in 2001.
Lukaku gathered the ball outside the penalty area, cutting inside Tom Schnell and then beating Chris Philipps before netting a composed left-footed finish.
Mario Mutsch had a diving header saved at the other end before Chadli grabbed his third international goal 19 minutes from time with a driven effort from just inside the penalty area.
And there was still time for De Bruyne to make his mark, converting from the spot after another debutant Divick Origi was felled in the area.
Belgium opens its World Cup campaign against Algeria on June 17.