The left-handed Miller (46 off 22 balls) and rising Indian talent Manohar (21-ball 42) put together 71 runs to steer Gujarat to a mammoth 207-6 in their home Ahmedabad.
The Miller-Manohar show, which included seven sixes, and an unbeaten five-ball 20 by Rahul Tewatia helped Gujarat get 94 runs from the final six overs of mayhem.
Man of the match Manohar said, "I think I have been gifted to time the ball well and I've been doing it from a young age and to do it at this level it feels special, it feels like a dream."
With their task cut out, Gujarat bowlers kept down five-time champions Mumbai to 152-9 as Afghanistan wrist spinners Rashid Khan and Noor Ahmad shared five wickets between them.
Gujarat, who had a fairytale debut season last year when they won the IPL, moved second in the table behind toppers and four-time winners Chennai Super Kings at the midway stage of the T20 tournament.
At the conclusion of the league stage, the top four teams will qualify for the playoffs. The final is on May 28 in Ahmedabad.
The evening belonged to the Gujarat batters after opener Shubman Gill set the tone for his team's domination with his 56 off 34 balls at the world's biggest cricket stadium.
Gill departed after his third fifty of the season and Miller and Manohar soon took over to tear into the opposition attack with a flurry of fours and sixes.
Both the batsmen were denied fifties but it was raining sixes by the end of the innings and the left-handed Tewatia joined in the charge in his team's highest IPL total.
Mumbai's Arjun Tendulkar, son of legendary Sachin Tendulkar, had some redemption from his previous match when he was hit for 31 runs in one over as the left-arm quick gave away nine in his two overs and took a wicket.
Rohit should 'take a break'
Mumbai were never in the chase after skipper Rohit Sharma fell caught and bowled, for two, to his opposite number Hardik Pandya and the wickets kept tumbling.
Former India captain Sunil Gavaskar suggested Rohit should take a break in the IPL to get fresh ahead of the World Test Championship final against Australia in June.
"I think he should take a break and return for the final three or four matches (for Mumbai this season)," Gavaskar said on Star Sports. "I don't really know what's on his mind."
Rashid struck twice with his leg spin in one over and was soon joined in by fellow Afghan Noor, an 18-year-old who returned figures of 3-37.
Mumbai's expensive Australian import Cameron Green made 33 before falling to Noor's left-arm wrist spin that soon got Tim David for a duck.
