[2][3][4][5] Wyle's parents divorced in the late 1970s, and his mother later married James C. Katz, a film restorationist[6] with three children of his own from a previous marriage.

[7] Edith R. Wyle was an expressionist painter who also created The Egg and The Eye, a café and shop in the Miracle Mile district of Los Angeles.

Wyle was first seen in the Paul Bartel 1985 film Lust in the Dust (a western exploitation/parody which starred Tab Hunter, Lainie Kazan, and Divine) as an extra in the local gang running the small town of Chili Verde.

He also appeared in the feature Swing Kids as Emil Lutz, a leader in the Hitler Youth, and in the independent movie The Myth of Fingerprints with Roy Scheider, Blythe Danner, and Julianne Moore.

Steve Jobs was so impressed with the performance that he invited Wyle to step on stage as him at the opening of his annual speech at the Apple convention.

Wyle starred as the lead in TNT's sci-fi series Falling Skies (2011-2015), Wyle played Tom Mason, a former Boston University history professor who becomes the second-in-command of the 2nd Massachusetts Militia Regiment, a group of civilians and fighters fleeing post-apocalyptic Boston while fighting aliens who have wiped out 90% of humanity.

For his work as one of the producers of 2005 Los Angeles Production of Michael John LaChiusa's The Wild Party, he won an NAACP Theatre Award.

[20] Wyle devotes much of his free time to the international non-profit organization Doctors of the World and to his work as a member of the Human Rights Watch Council.

Wyle also serves as the voluntary artistic producer of the Blank Theatre Company in Hollywood, which stages an annual young playwrights festival and whose alumni include Ed Asner, Sarah Michelle Gellar, D. B. Sweeney, James Kerwin, Amber Benson, Megan Henning, Travis Schuldt, Warren Davis, Grant Show, and Nicholas Brendon.

Wyle was the spokesperson for the Cover the Uninsured campaign in 2004, which had as Honorary Co-Chairs former Presidents Gerald Ford and Jimmy Carter.

The Cover the Uninsured Week is annually held in the United States of America and focuses attention on the nearly 44 million Americans who go without health care coverage.

In 2009, Wyle became a spokesperson for the World Wide Fund for Nature (WWF), saying that polar bears are "hanging on by a thread" and "may be extinct in our children's lifetime, due to the effects of climate change.

[23][24] Just after Donald Trump won the 2016 general election, Wyle along with other actors participated in a video released by Unite for America, making a heartfelt appeal to the Republican presidential electors of the Electoral College to swing their votes away from President-elect Donald Trump so the House of Representatives could select what Wyle and others referred to as a qualified candidate for the presidency.