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The team changes suggested the home side would be favourites, but not the scale of the one-sided encounter that followed.
Middlesex recalled Roland-Jones for Jack Nelson, while Glamorgan gave debuts to two seamers - 18 year old academy product Tom Edwards and Aussie Connor O'Riordan, who has been on an extended second team trial.
Both teams have five players at the Hundred, but Glamorgan also chose to rest the overworked Timm van der Gugten as well as veterans Colin Ingram and Chris Cooke, with Zain ul Hassan on paternity leave, teenage prodigy Tom Norton missing at least most of the competition with a back issue, Jamie McIlroy suffering a late minor niggle in the warm-up, and Billy Root not selected.
Sharma was quickly into his stride having Callum Nicholls adjudged lbw, but with Byrom getting the ball away for six fours, Glamorgan got to 44 before they fell apart, losing wickets in six consecutive overs.
Sharma had Henry Hurle (10) caught by keeper Joe Cracknell, Jack Hope-Bell caught to mid-off and Will Smale given lbw.
Meanwhile Roland-Jones induced Byrom (29) and Dan Douthwaite to edge to slip, Sam Robson snaffling two smart grabs, while Alex Horton feathered a catch behind.
Roland-Jones bowled his 10 over allocation straight through, while Sharma was replaced after seven by Cornwell, who wrapped up the last three while Cracknell finished with four catches.
The difficult bounce did not excuse the extent of Glamorgan's struggles against an accurate seam attack.
With 20 coming off a nervous first over from O'Riordan, Josh de Caires got Middlesex off to a flyer.
Captain Andy Gorvin took himself off after just two overs just to give Edwards a bowl on his unexpected debut, but the 50 came up in just six overs as De Caires and Nathan Fernandes were able to attack with freedom.
Fernandes (14) drove Edwards to mid-on to give the youngster a first senior wicket, and a second quickly followed when Sam Robson was caught behind.
But De Caires (45 not out off 30) hit the winning run off the first ball of the 10th over to complete the rout.
Middlesex next travel to Worcester on Friday 31 July.
Glamorgan are set to come up against former England captain Ben Stokes at Durham on Wednesday, with further away fixtures against Derbyshire and Hampshire to follow as they try to rebuild confidence.
Middlesex seamer Naavya Sharma said:
"Potentially there was a bit more (life) in the pitch than we expected, but having played here a few times, there's always a little bit in it bowling first with a bit of cloud cover and grass on the pitch.
"Ro-Jo (Roland-Jones) has done it for years, finding the perfect length and it was nice for me to find it as well. Having him at the other end is always superb, he's always chatting to you and telling you whatlengths to bowl and keeping you calm.
"Chuffed with three wins in three, it's the perfect start for us and the best thing is it's different blokes standing up every game. It's a great start to the campaign and hopefully we can keep it up."
Glamorgan acting head coach David Harrison told BBC Sport Wales:
"Everyone is very disappointed, we clearly weren't good enough at all. There was enough in the wicket but it wasn't a pitch where you should be all out for that score.
"We've had a couple of games where we've been four or five down early and it's happened again so it's something we need to sort out quickly.
"It's a reasonably inexperienced team but there is enough experience in the group to be able to score more.
"You've got to get the positives somewhere and it was great to see Tom get his debut having couple through the academy and the pathway, he bowled really well and deserved his two wickets."
