Australia declared at 5-233 soon after lunch on Sunday when Usman Khawaja was caught at deep third man for 90.
Mitch Marsh finished unbeaten on 63 off 68 balls, following his impressive 90 in the first innings.
There were plenty of demons in the wicket on day four, with Marsh sustaining two blows to the helmet and Khawaja painfully struck on his right arm.
Chasing 450 for victory, Pakistan were rolled for 89 in 30.2 overs, with Starc (3-31), Josh Hazlewood (3-13) and Lyon (2-14) sharing the spoils.
The most memorable moment belonged to Lyon, who had to wait until his seventh over of the day before claiming the wicket he needed to get to 500 Test scalps.
View this post on Instagram A post shared by cricket.com.au (@cricketcomau)
Lyon's lbw shout against Faheem Ashraf was initially turned down, but Australia's review proved successful as the ball-tracking technology showed the ball would have hit leg stump.
The crowd erupted and Lyon was hugged by each of his teammates when the DRS decision was handed down.
Lyon joined greats Shane Warne (708 wickets) and Glenn McGrath (563) as Australians to have cracked the magical 500 barrier.
The 36-year-old offspinner had his second wicket of the innings four wickets later when his delivery stayed low and crashed into the stumps to dismiss Aamir Jamal.
Pakistan's hopes of pulling off the largest successful fourth-innings run chase in Test history evaporated early as Starc removed openers Abdullah Shafique and Imam-ul-Haq.
Babar Azam fell to Pat Cummins for 14 shortly before lunch, and Pakistan were in dire straights at 5-56 when Sarfaraz Ahmed edged Starc to gully.
Salman Agha was run out following a disastrous mix-up to make it 6-63, and from there it was the Lyon and Hazlewood show as Australia stormed to victory and a 1-0 lead in the three-Test series.
Usman Khawaja made a sparkling 90 to help Australia set Pakistan a near impossible run chase. (Richard Wainwright/AAP PHOTOS)
Earlier in the day, Khawaja required medical treatment after being hit just below his right elbow by a 136km/h Aamir Jamal delivery.
A sizeable bump soon formed on Khawaja's arm, but he bravely batted on to guide Australia safely to lunch.
On a busy morning for DRS, Steve Smith (45) was left cursing his luck after ball-tracking showed Khurram Shahzad's delivery was going to clip the top of the leg-stump bail by the barest of margins.
Smith repeatedly shook his head in frustration as he trudged off the ground.
Khawaja was 40 when given out lbw after being struck on the pads by a swinging Jamal delivery, but his review was successful given the ball had made contact marginally outside the line of off stump.
Mitch Marsh blasted a quickfire 64 not out in Australia's second innings against Pakistan. (Richard Wainwright/AAP PHOTOS)
Marsh was given a life on 23 when Pakistan captain Masood dropped a straightforward chest-high catch at mid-off.
Khawaja went to lunch on 68, and Pat Cummins held off on a declaration call to allow the opener to reach his century.
But with 10 more runs needed, Khawaja slashed at a wide Shaheen delivery and was easily caught.
MOST TEST WICKETS BY AN AUSTRALIAN:
708 - Shane Warne
563 - Glenn McGrath
501 - Nathan Lyon*
355 - Dennis Lillee
338 - Mitchell Starc*
313 - Mitchell Johnson
(* denotes: still playing)
