On a slow wicket where the ball gripped and spun, Nawaz recorded career-best figures of 4-18 to bowl out the West Indies for 155 with more than 17 overs to spare.
Pakistan skipper Babar Azam (77) and Imam-ul-Haq (72) continued their sublime batting form and scored half centuries before Akeal Hosein bagged 3-52 to restrict the home team to 275-8.
Shamarh Brooks top-scored with 42 and Kyle Myers added 33 against the pace before Nawaz ran through the top-order to give Pakistan an unassailable 2-0 lead in the three-match series.
“We were confident at the break that we could defend this,” Babar said.
“Nawaz took wickets at crucial times. We were under pressure after the first 10 overs but really happy with the way we fought back.”
Brooks and Myers batted aggressively against fast bowlers and added a rapid 67 runs off 54 balls despite Shaheen Shah Afridi dismissing first-match century-maker Shai Hope for just 4 in the first over.
Mohammad Wasim Jr. (3-34), replacing Hasan Ali in the Pakistan XI, broke through when he clean bowled Myers before Nawaz had Brandon King bowled off his fourth ball.
Nawaz extracted sharp turn and also accounted for the wickets of Brooks, who was trapped lbw and then had Rovman Powell (10) and skipper Nicholas Pooran's (25) wickets in one over.
Wasim and Shadab Khan (2-40) then wrapped up the tail quickly to give Pakistan a massive win.
“I was focusing on the basics and the pitch assisted me," Nawaz said.
“The ball was turning, we had an idea in the first innings, particularly after I got out ... I want to do well as an all-rounder and improve day by day."
Earlier, Babar, who won the toss and chose to bat on another sweltering hot day in Multan, and Imam added 130 runs for the second-wicket stand after Fakhar Zaman yet again fell cheaply for 17.
Babar shared fourth consecutive century partnership in ODIs with Imam but just when it looked like the game would drift away from the West Indies, Imam got run out in a mix-up with his skipper.
Imam had nearly made his ground at the non-striker's end but Babar was ball watching instead of responding to Imam's call.
Babar looked to pace the innings in testing conditions with the temperature touching to 45 degree Celsius but the West Indies came back strongly in the latter half of the Pakistan innings.
Babar, who scored a century in a five-wicket win on Wednesday, fell to Hosein's sharp turning delivery and offered a tame return catch off a leading edge to the bowler as Pakistan lost four quick wickets in space of 20 runs.
Hosein clean bowled Mohammad Rizwan (15) around his legs and Nawaz (3) was caught in the leg slip with Mohammad Haris' run-a-ball six-run knock ended when he gloved Alzarri Joseph (2-33) to wicketkeeper Hope.
Left-handed Khushdil Shah couldn't repeat his power-hitting from Wednesday, when he carried Pakistan home with a superb unbeaten 41 off 23 balls, and was clean bowled by Anderson Phillip for a struggling 22 off 31 balls in the penultimate over as West Indies gave away just 67 runs in the last 10 overs.
“Tough day for us," Pooran said after yet again failing with the bat.
“Credit must be given to Nawaz who bowled really well. It was definitely a challenging wicket (and) there were some soft dismissals, it wasn't our day."