Ronaldo ended his six-match goal drought with his ninth Premier League goal of the season to give United control after a flagging performance in the first half, before Fernandes fired home after a quick break in the dying embers of the match.
Brighton added to a woeful record at Old Trafford that has now seen 12 defeats and two draws, and will be frustrated with a period, shortly after the break, that saw a gifted goal followed by a red card to captain Lewis Dunk.
Moments later, Dunk brought down Anthony Elanga and was sent off having been adjudged to have prevented a goalscoring opportunity after a VAR review.
After a formidable away record saw only one league defeat previously - to Aston Villa - Brighton will be disappointed by the manner of the uncharacteristic spell that proved detrimental to their efforts in Manchester.
Story of the match
Both sides had chances throughout the opening passage of play, with Brighton the team dictating possession and probing for an opener to aid a maiden victory at Old Trafford.
After displaying their trademark fluidity resilience, Albion entered the break with optimism that the unwanted record at Old Trafford could be ended.
Robert Sanchez had a busy night in the Brighton net, acrobatically preventing a fierce Ronaldo header and redeeming a careless error with a fine save against Fernandes.
United are still not at their cohesive, ferocious best, but victory on Tuesday night certainly aids their prospects for the rest of the campaign, and appeases a hungry fanbase.
United ease worries over bid for top-four
United have been under intensifying pressure under Ralf Rangnick, but grabbed a vital victory against a resilient Brighton side and reaffirmed their claim for a spot in next season's Champions League.
It wasn't perfect, but the ability to grab a lead and maintain it has been something that has evaded United in times this season, and the squad will be galvanised by elements of the performance.
Lapse in concentration proves fatal
Graham Potter will have been incensed by his side's costly blunder, with Dunk's dismissal effectively nullifying the good work that had been on offer throughout the first half.
Despite this, Brighton continued their tenacious approach and came close through Moder's second half effort, deflected against the crossbar.
The result will sting for Albion after good work in the first half, and the snapping of a seven-match unbeaten run reminds the club that there is work still to be done for an improving side.
Next time out
Both teams return to Premier League action at the weekend, with Brighton hosting bottom club Burnley on Saturday and United travelling to fierce rivals Leeds United the following day, with hopes of strengthening their position in the top-four.