Elwes has appeared on television in a number of series including The X-Files, Seinfeld, From the Earth to the Moon, Psych, and Life in Pieces.

Through his maternal grandfather, Elwes is also related to Sir Alexander William "Blackie" Kennedy, one of the first photographers to document the archaeological site of Petra following the collapse of the Ottoman Empire.

[21] Elwes made his acting debut in 1984 in Marek Kanievska's film Another Country, which was loosely based on the English boarding school exploits of British spies Burgess, Philby and MacLean.

[11] He then played Guilford Dudley in the British historical drama film Lady Jane, opposite Helena Bonham Carter.

The following year Elwes was nominated for a Golden Satellite Award for Best Performance by an Actor in a Mini-Series or Motion Picture Made for Television for his portrayal of Colonel James Burton in The Pentagon Wars directed by Richard Benjamin.

Elwes had a recurring role in the final season (from 2001 to 2002) of Chris Carter's hit series The X-Files as FBI Assistant Director Brad Follmer.

In 2003 Elwes portrayed Kerry Max Cook in the off-Broadway play The Exonerated in New York, directed by Bob Balaban (18–23 March 2003).

The following year, Elwes played the young Karol Wojtyła in the CBS television film Pope John Paul II.

[27] He made an uncredited appearance as Sam Green, the man who introduced Andy Warhol to Edie Sedgwick, in the 2006 film Factory Girl.

[28] Also in 2009 Elwes joined the cast of Robert Zemeckis's motion capture adaptation of Charles Dickens' A Christmas Carol portraying five roles.

That same year he was chosen by Steven Spielberg to appear in his motion capture adaptation of Belgian artist Hergé's popular comic strip The Adventures of Tintin: The Secret of the Unicorn.

[29] Elwes's voice-over work includes the narrator in James Patterson's audiobook The Jester,[30] as well as characters in film and television animations such as Quest for Camelot, Pinky and The Brain, Batman Beyond, and the English versions of the Studio Ghibli films, Porco Rosso, Whisper of the Heart and The Cat Returns.

[31] The following year Elwes portrayed the part of Gremlin Gus in Disney's video game, Epic Mickey 2: The Power of Two.

[34] and the following year Elwes joined Selena Gomez for the comedy ensemble, Behaving Badly directed by Tim Garrick.

The book featured never-before-told stories, exclusive behind-the-scenes photographs, and interviews with co-stars Robin Wright, Wallace Shawn, Billy Crystal, Christopher Guest, Fred Savage and Mandy Patinkin, as well as screenwriter William Goldman, producer Norman Lear, and director Rob Reiner.

[36][37] In 2014, Elwes co-wrote the screenplay for a film entitled Elvis & Nixon, about the pair's famous meeting at the White House in 1970.

[40] In April 2018 Elwes portrayed Larry Kline, mayor of Hawkins, for the third season of the Netflix series Stranger Things, which premiered in July 2019.

[44] Elwes and his family lost their home in the Palisades Fire during the January 2025 Southern California wildfires, but evacuated safely.

[45] In March 2021, Elwes posted on his social media accounts that his younger half-sister Milica had died after battling Stage 4 cancer for more than a year.

[47][48] According to the Hollywood Reporter, Elwes initiated the 2020 fundraiser that re-united many Princess Bride cast members to support Joe Biden in the battleground state of Wisconsin.