It was a night to forget for former Sassuolo boss De Zerbi on his first return back to his native Italy as a manager, as the Seagulls suffered the heaviest defeat by an English club in Europe for five years.
Several defensive errors proved costly for Brighton at the Stadio Olimpico, as goal from Paulo Dybala, Romelu Lukaku, Gianluca Mancini and Bryan Cristante have put Roma firmly in the driving seat to secure a place in the quarter-finals.
Brighton have now lost three successive matches across all competitions for the first time under De Zerbi, while it is the first time the 44-year-old has been beaten in three straight games as a coach since January 2020 (a run of three with Sassuolo).
Reflecting on the disappointing result, De Zerbi told reporters: "We played our game and we gave our best and maybe now our best at this moment is this performance.
"Roma were much better in terms of showing their experience of playing this type of game and we suffered too much at this level of the competition, which we're not used to.
"We lost against a stronger team than us. Roma players are used to playing this kind of match. I am Italian. I know these players, they were already good players.
"We created a lot of chances - the same perhaps in numbers - but Roma played with a different speed and habits to win the game. It's the first time Brighton played in the Europa League last 16 - it's a big level for us.
"Today is the day I love my players the most. I know we played 20% less than our potential. It is an important lesson for all the club to learn from this game.
"For the president, because in the future we will be able to improve the team. For myself, because maybe I will better handle the period from January to March, especially in England with such a busy schedule.
"And for the players. Today they walk away with many regrets and, when you have regrets, you know what you can expect and you can improve and you want to do better. We lost deservedly to a better team - better also mentally.
"Now the focus is on Nottingham Forest [on Sunday]. We have to keep going because we want to compete in the Premier League for the rest of the season."
Playmaker Pascal Gross, who played the full 90 minutes, has acknowledged that Brighton were left to rue the costly defensive mistakes made in the Italian capital, but he remains upbeat ahead of next week's second leg on home soil.
"We felt we prepared like we always do and we felt really positive before the game," said Gross. "I think we conceded a couple of goals which at this level you will get punished for and we didn't score ourselves.
"We lost the ball in bad areas and we lost some duels, which can happen at this level. All you can do is try and get better. In football everything is possible, but we have another 90 minutes on Sunday first."
Brighton will look to avoid a fourth consecutive loss without scoring in all tournaments when they welcome Nottingham Forest to the American Express Stadium for a Premier league clash on Sunday.