Miller-Uibo was superb in the two-lap indoor event, powering out of the blocks and keeping it going.
Wadeline Jonatas chased in vain as Miller-Uibo won in a new Bahamian national record of 50.21s, the fastest time in the world this year, with Jonatas second in 51.95s.
Afterwards, the Rio 2016 Olympic champion said, "We just came out here to see where we were at and get a nice race in. I felt really strong and overall I'm very pleased with the race. We're just glad where we're at right now."
Lyles used the 60m heats to warm up for the 200m final later in the meet, clocking 6.76s in his first indoor race for three years.
But he was below his best in the one-lap contest, clocking 20.80s with Deon Lendore of Trinidad and Tobago just behind in 20.92s.
Speaking in the post-race mixed zone, Lyles said, "I haven't run an indoor 200 for a long time so it is what it is and just keep moving on. I definitely haven't done a lot of it in recent years and it takes a little while to get back into it.
"We've been training for a lot of strength and endurance and it obviously paid off because I was able to come into the 60, warm up, and then I was able to shake off any type of fatigue I had from it.
"To be honest, I still feel really good even coming off the 200, I could run three more. I actually feel strong which is really what we were trying to get out of training." - Noah Lyles
When asked about the speculation surrounding the Tokyo 2020 Olympic Games going ahead this summer, Lyles replied, "It's one day at a time. The Olympics are said to be happening and I'm going to train like they're going to happen. And if they don't then I'll just keep training through, go to any races I can just like we did last year in 2020, and then get ready for World Champs because they're going to be in the USA."
Lyles was behind Trayvon Bromell in the 60m heats, and the American sprinter kept up his excellent recent form by winning the final in 6.50s clear of Demek Kemp and Maurice Eaddy.
National records tumble in New York
The NB Indoor Grand Prix was held in New York with its normal home, the Reggie Lewis Center in Boston, being used as a mass COVID vaccination site.
World 800m champion Donavan Brazier broke his own national indoor record by 0.01s, charging clear on the final lap to come home in 1:44.21.
Jamie Webb of Great Britain was second in a personal best of 1:46.26.
Elle Purrier smashed the American two-mile record by eight seconds, clocking 9:10.28 with 2017 world 3000m steeplechase champion Emma Coburn in second place and also inside Jenny Simpson's mark from 2015.
When asked if she might step up to 5000m, Purrier said, "I'm just having fun being able to find variability in my races. My heart is in the mile and the 1500m but we'll just keep going with our plan and figure it out later."
There was also an American record in the men's 1000m with Bryce Hoppel winning in 2:16.27, just inside the late David Torrence's mark from 2014.
Oliver Hoare took the 1500m in a new Australian record of 3:32.35, powering past long-time leader Jake Wightman with 100m to go.
"I just really wanted to run under the Olympic standard and I went well under that today. I know a lot of the boys have been talking about it... magic's going to happen when people have been waiting and itching to race."
Kayla White won the women's 60m in a personal best of 7.15s, but the final was marred by a false start for Aleia Hobbs who was disqualified after clocking 7.10s in the heats.
Hannah Cunliffe was second in 7.17s with Candace Hill third in 7.19s.
Olympic and world silver medallist Sandi Morris took the pole vault with a third-time clearance at 4.60m but then had three failures at 4.75m.
Afterwards, she said that the vaulters struggled because the box where they plant the pole was shallower than normal.
She said, ""We had to jump on very small poles, all four of us. When something like that happens across the board, you know that, 'OK, it's not just me.'
"If I'd had smaller poles in my bag today, I'd have used those. Honestly, I'm just happy came away safe today because coming down in the box can be very dangerous."
When asked about whether she thought the Tokyo 2020 Olympic Games would take place this summer, Morris responded, "I don't think you're going to hear a single Olympic athlete say we don't want to have the Olympics. I'm not a scientist or a medical professional so I'm going off my emotions as an athlete.
"I'm hoping that we've learned enough about COVID-19 that we can execute the Olympics in a healthy way that is not going to put the public at risk."
She added, "I also think athletes would choose to have an Olympics with no fans rather than no Olympics. I know I would."
Michael Norman just got the better of room-mate and training partner Rai Benjamin in the 400m, taking victory in 45.34s.
Norman was some way outside his American record of 44.52s set in 2018 which was not ratified as a world record due to a lack of drug testing at the venue.
He said afterwards, "The main purpose of today was to compete and have fun, and to knock the cobwebs off because it's been over a year since I've run that distance.
"Typically, I probably would not have run an indoor event but due to all of last year being postponed I just wanted to get ahead and compete at this distance again and get my legs back into this 400 rhythm."
Trey Culver equalled his personal best of 2.33m in the high jump, the best clearance in the world this year, winning from fellow Americans Jeron Robinson and Erik Kynard.
In what she revealed afterwards would be her sole indoor meet of the year, world 110m hurdles record holder Kendra Harrison scorched to victory in the 60m hurdles in a 2021 lead time of 7.82s.
Britain's Tiffany Porter was tied for second with Gabrielle Cunningham in 7.89s, the latter recording a new personal best.
Harrison won silver at the 2019 World Championships in Doha but missed Rio 2016 after finishing sixth in the U.S. Olympic trials.
Sydney McLaughlin, the 2019 world silver medallist at 400m hurdles, was back in eighth place in 8.56s and revealed afterwards that she had been hurdling with her non-dominant leg.
She said afterwards, "I think it's something we've been thinking about for a while, being able to hurdle efficiently with both legs and what better way to do that then the short hurdles.
"It was good to get into a fast race and really be forced to use it without being able to think that much."
Her brother Taylor was fourth in the 300m with victory going to Trinidad and Tobago's 2017 4x400m relay gold medallist Jereem Richards in 32.71s.
The 200m specialist went back to Trinidad in March last year for two weeks for a sponsorship appearance and ended up stuck there for eight months due to COVID lockdown.
He said, "It's just a blessing to be back and able to compete. Last year, I didn't get a chance to run at all.
"I didn't have access to a track. I was training in the street, up the hill, at my father-in-law's home gym... there really wasn't much to work with. I enjoyed the time that I had back home though."
Ajee Wilson finished strongly to take the 800m in 2:01.79, showing little sign of a hamstring injury suffered last week.
Long-time leader Kaela Edwards was second with Britain's Isabelle Boffey clocking a personal best 2:02.45 in third.
Wilson, who was favourite for the 2019 World Championships 800m before being stunned by Uganda's Halimah Nakaayi, did not race at all last summer, saying she "just didn't feel comfortable going out. I interact with a lot of people who are super at-risk".
Gabby Thomas won the women's 300m in a world-leading time of 35.73s which was also a new personal best.