After gaining recognition for playing supporting parts in Robin Hood (2010) and Drive (2011), Isaac had his breakthrough with the eponymous role of a singer in the musical drama Inside Llewyn Davis (2013), which earned him a Golden Globe nomination.

Isaac's career progressed with leading roles in the crime drama A Most Violent Year (2014), the thriller Ex Machina (2015) and the superhero film X-Men: Apocalypse (2016).

On television, Isaac was the lead in three miniseries: Show Me a Hero (2015), in which his portrayal of Nick Wasicsko won him a Golden Globe Award, Scenes from a Marriage (2021), and the Marvel Cinematic Universe's Moon Knight (2022).

[9] Drawn to creating music and film content since a young age, he struggled growing up in Miami, which in his view was not "a flourishing place for the arts" due to its rather conservative nature.

[5] He learned music, played guitar and continued to make home movies, inspired by Quentin Tarantino's work: "action [films], with lots of blood and cars".

[22][23][24] After graduating from Juilliard, Isaac continued to write music and performed in small New York clubs, and played Proteus in Two Gentlemen of Verona (2005) in The Public Theatre.

[16] The following year, he portrayed Federico García Lorca in New York City Center's production of Beauty of the Father; David Rooney of Variety remarked that his "injection of wry humor provides welcome levity".

[25] Also in 2006, he briefly appeared on the television series Law & Order: Criminal Intent,[26] and played Joseph in the biblical epic The Nativity Story, opposite Keisha Castle-Hughes.

[35][36] In a book published by Rutgers University Press, which analyzes the performances of rising actors in the 2010s, Rick Warner believed that Isaac "momentarily steals the scene" as a United Nations interpreter in Che.

[40] Rick Warner wrote, "In his early minor film roles, Isaac makes the most of the few lines he is given, supplying emotional complexity not just verbally but also through his attractive face and piercing stare.

His first, the Mexican epic historical drama For Greater Glory, had him play a freedom fighter,[54] for which he was nominated for an ALMA Award for Favorite Movie Actor – Supporting Role.

[62][63] In 2013, Isaac played the titular character of a struggling folk singer in 1961 Greenwich Village in the Coen brothers' musical drama Inside Llewyn Davis.

[69] A. O. Scott of The New York Times wrote, "Isaac, a versatile character actor here ascending to the highest levels of his craft, refuses the easy road of charm.

[78][79] Ann Hornaday of The Washington Post praised Isaac for "deliver[ing] a master class in that skill from the very first moment of A Most Violent Year to the last", adding, "he's a commanding screen presence, even when he's saying nothing.

[100] Critics Angelica Jade Bastién and Glenn Kenny believed Isaac, though a "charismatic and dynamic" actor, "feel[s] so torpid here",[101] and "fares poorly through no fault of his own".

[99] Also in 2016, he starred alongside Charlotte Le Bon and Christian Bale in The Promise, a historical drama about a love triangle set during the Armenian genocide.

[105] Richard Roeper of the Chicago Sun-Times wrote that the film was "derivative of better war romances" but was "bolstered by strong performances from Isaac and Bale, two of the best actors of their generation".

[124] Isaac debuted as a producer filming the historical drama Operation Finale (2018), in which he played Peter Malkin, the Israeli secret agent who captured Nazi fugitive Adolf Eichmann in 1960.

[36][129][130] Isaac co-starred with Olivia Wilde in the box-office failure Life Itself; Caroline Siede of Consequence found the two leads unconvincing and their roles to be poorly written.

[129][131] After Isaac finished filming Star Wars: The Rise of Skywalker in October 2018, he intended to take a prolonged acting hiatus but was cast as Duke Leto Atreides in Dune (2021) a few months later.

[143] Roktim Rajpal of the Deccan Herald believed that Isaac "is the backbone of the short and makes an impact with his sincere performance", yet he fails to "internali[z]e the character as much as expected".

[150] To avoid what he saw as "green screen alien space land", Isaac starred as William Tell—a troubled, gambling military veteran—in the Paul Schrader-directed crime drama The Card Counter.

[151][152] Justin Chang of NPR lauded Isaac for "bring[ing] his usual sly, soulful magnetism to the role" and embodying his character's trauma in his "dark, haunted gaze".

[168] In a review of the fifth episode, Matt Fowler of IGN took note of Isaac's "dynamic and dazzling performance" and "ace acting", highlighting the dramatic scene in which his character revisits his traumatic past.

"[163] Brett Martin of GQ commented on his "wide, easy smile", adding, "It's been a long time since we've had a leading man whose charisma comes packed with such tetchiness, so little naked desire to be liked.

"When I think about what makes him so credible as an actor", wrote the list's co-author A. O. Scott, "[is] whatever Isaac is pretending to do onscreen [...] I always believe that he really knows how to do it, and that I'm watching some kind of authentic mastery in action.

"[184] Hossein Amini, who directed Isaac in The Two Faces of January, remarked on his "ability to make the tiniest shifts in character incredibly quickly, without revealing any element of process".

[185] Martin identified an extent of "loneliness and menace" in Isaac's most memorable characters, attributing his growing success to "a series of brilliant but darkly idiosyncratic roles" (Inside Llewyn Davis and A Most Violent Year).

[52] Tom Shone of The Guardian identified common characters of "ambitious, slightly myopic men whose own movement quickens their fall" (an oil importer struggling to keep his business intact in A Most Violent Year and a doomed politician in Show Me a Hero).

Rick Warner opined Isaac has "skillfully embodied several different affective dispositions—sensitive, flippant, romantically charming, hyperintelligent, neurotic, cynical, sinister, and menacingly violent".