Messi sat out Argentina's 2-0 win over Italy in Manchester last week but is expected to feature in the game at the Wanda Metropolitano.
And while the inclusion of the deadly 30-year-old could make it a busy night for De Gea, the Manchester United shot-stopper is not daunted by the prospect.
"As a goalkeeper it is a challenge to face Messi," De Gea said.
"But we want the best players to be on the pitch and Messi is one of them. It's always special to play against him."
Bayern Munich's Thiago Alcantara, Messi's former team-mate at Barca, offered a reminder that the five-time Ballon d'Or winner is not La Albiceleste's only threat, but does boast the capacity to prove decisive.
"Messi is one of the determining factors within the Barca [team] and the [Argentina] national team, but the team is more [than just Messi]", he said.
"Argentina knows how to press, play, and when attacking, they are animals.
"In addition, above [that] they have that Leo factor that can mark more [distinctly] the differences [between the teams].
"It is a determining factor."