He returned to Broadway acting in the comedic play Luv (1964), and directed Neil Simon's The Sunshine Boys (1971), for which he received a Tony Award nomination.

He also acted in Wait Until Dark (1967), Inspector Clouseau (1968), Popi (1969), Catch-22 (1970), The In-Laws (1979), Edward Scissorhands (1990), The Rocketeer (1991), Glengarry Glen Ross (1992), Grosse Pointe Blank (1997), Thirteen Conversations About One Thing (2001), Get Smart (2008), Going in Style (2017), Dumbo (2019) and Spenser Confidential (2020).

Arkin voiced Schmendrick in The Last Unicorn (1982), J. D. Salinger in the animated series BoJack Horseman (2015–16), and Wild Knuckles in Minions: The Rise of Gru (2022).

During the 1950s Red Scare, Arkin's parents were accused of being Communists, and his father was fired when he refused to answer questions about his political ideology.

Critic Howard Taubman of The New York Times gave the play a mixed review but praised Arkin's performance, describing it as "a choice specimen of a shrewd actor ribbing his profession.

The film focuses on a Puerto Rican widower struggling to raise his two young sons in the New York City neighborhood of Spanish Harlem.

[38] Arkin and his second wife Barbara Dana appeared together on the 1970–1971 season of Sesame Street as a comical couple named Larry and Phyllis who resolve their conflicts when they remember how to pronounce the word "cooperate".

[40][41] Written by cartoonist Jules Feiffer, it is a black comedy film starring Elliott Gould and Marcia Rodd about a girl, Patsy (Rodd), who brings home her boyfriend Alfred (Gould) to meet her dysfunctional family amid a series of random shootings, garbage strikes, and electrical outages ravaging the neighborhood.

Roger Ebert's review in the Chicago Sun-Times was enthusiastic, stating "One of the reasons it works and is indeed a definitive reflection of America's darker moods is that it breaks audiences down into isolated individuals, vulnerable and uncertain.

[27] During the 1970s, Arkin starred in films of various genres including the Vernon Zimmerman road comedy Deadhead Miles (1972), the Gene Saks adaptation of the Neil Simon play of the same name Last of the Red Hot Lovers (1972) with Sally Kellerman and Paula Prentiss, the black comedy action film Freebie and the Bean (1974), the dramedy Rafferty and the Gold Dust Twins (1975) with Kellerman and Mackenzie Phillips, the 1978 TV prison film The Other Side of Hell (1978), the western comedy Hearts of the West (1975),[45] and the British mystery The Seven-Per-Cent Solution (1976).

[48] In 1980, Arkin starred in the Marshall Brickman comedy Simon which gained mixed reviews but earned him a Saturn Award nomination.

[52] He won Best Supporting Actor at the Genie Awards for his role as Reuben Shapiro in the 1985 film adaption of Mordecai Richler's semi-autobiographical novel Joshua Then and Now.

[26] In 1990, Arkin appeared in a supporting role in Tim Burton's fantasy romance Edward Scissorhands starring Johnny Depp and Winona Ryder.

[63] In 1996, Arkin appeared in the film adaptation of the Kurt Vonnegut novel Mother Night starring Nick Nolte, Sheryl Lee, John Goodman, and Kirsten Dunst.

[64] The following year Arkin appeared in the comedy Grosse Point Blank starring John Cusack as well as the dystopian science fiction film Gattaca with Ethan Hawke.

[65][49] In 2001, he appeared in the comedy America's Sweethearts starring John Cusack, Julia Roberts, Billy Crystal, and Catherine Zeta-Jones.

[66] He also starred in the Jill Sprecher drama Thirteen Conversations About One Thing with Matthew McConaughey, John Turturro, and Clea DuVall.

[70][71] In 2006, Arkin appeared in a supporting role in the ensemble comedy-drama Little Miss Sunshine with Greg Kinnear, Steve Carell, Toni Collette, Paul Dano, and Abigail Breslin.

[74][75] In 2008, he appeared in the comedy films Sunshine Cleaning with Emily Blunt and Amy Adams,[76][77] Get Smart with Steve Carell, Anne Hathaway, and Dwayne Johnson,[citation needed] and Marley & Me starring Owen Wilson and Jennifer Aniston.

[78][79] The following year, he appeared in Rebecca Miller's The Private Lives of Pippa Lee[80][81] and Raymond De Felitta's City Island (both 2010).

For his performance, he received his fourth Academy Award nomination, his second for Best Supporting Actor, losing to Christoph Waltz in Django Unchained.

[90] He continued to act in supporting roles in films such as the sports drama Million Dollar Arm (2014) with Jon Hamm and the Christmas comedy Love the Coopers (2015).

[97] His final performance was voicing the character as Wild Knuckles in the Universal animated film Minions: The Rise of Gru, which was released to critical and commercial success.

[98] In September 2022, Arkin joined Casey Affleck, Kathy Bates, and Teyana Taylor who had been cast in the independent heist thriller The Smack, which was in pre-production prior to his death.

[102] He also performed the role of Dr. Pangloss in a concert staging of Leonard Bernstein's operetta Candide, alongside Madeline Kahn's Cunegonde.

[108] Beginning in the late 1990s,[109] he and Suzanne maintained a seasonal home in Cape Breton Island in the Canadian province of Nova Scotia.

In 2014, Arkin received the Gregory Peck Award for Cinematic Excellence to honor his life's work at the San Diego Film Festival.