Denied a wicket despite some good spells in Pakistan's first innings 302, Lyon smashed through their defences on a docile pitch, removing Shaan Masood and Asad Shafiq before tea after both scored defiant half-centuries.
The Adelaide Test has marked the first time since last summer Australia have kept the same bowlers together for two consecutive games, after rotating them through the Ashes.
The left-armer has also taken the most first-class wickets by an Australian in day-night matches, with his tally now at 58.
Called to follow on after reaching 302 in response to Australia's 589-3 declared, Pakistan's batsmen battled hard at the Adelaide Oval but were bowled out for 239 in their second innings shortly after the dinner break of the day-night test.More news: Migration issue is politically urgent for EU Commission leader
Pakistan were resilient, fighting out nearly five hours on day four but in the end it was futile after Australia 3 (dec)-590 batted them out of the match on the first two days.
On Day 2 of the Adelaide Test that belonged entirely to David Warner, Australia captain Tim Paine managed to attract the limelight for a while by taking a blinder behind the stumps.
Starc's bowling will be well overshadowed by David Warner's record-breaking 335 not out in Adelaide, but his form turnaround is nearly equally as impressive.
The new pink ball was taken when they returned and with the lights on it didn't take long to finish off the tail, with Hazlewood clean-bowling Mohammad Rizwan for 45 and Mohammad Abbas run out.More news: Injuries, ejection drain No. 4 Georgia for SEC title game
But Lyon struck again, with Shafiq getting a thin edge to a flighted ball that carried to Warner at slip and he was gone for 57.
Yasir Shah had provided some fight with his maiden century, but eventually fell for 113, while Babar Azam added 97.
Warner's triple century was the highlight while Labuschagne shored up his burgeoning reputation by making 162 to go with the 185 he made in the first Test at Brisbane.
Mitchell Starc has again been the star with 6-66 in the first innings and 1-10 in the second, stamping his authority as one of Australia's leading paceman again.More news: Simon Cowell, AGT Answer Allegations of Racial Discrimination Over Gabrielle Union Firing
Australia's next assignment is when they take on New Zealand in a three-match series at home.