Critics were universally positive in their reviews, describing the science fiction film as "one of the most satisfying shorts since Chris Marker's landmark 1962 La Jetee and almost certain to be the highlight of this year's Sundance, full stop," "dazzling, enthralling" and "astonishing."

Hertzfeldt was born on August 1, 1976 in Alameda County, California, the son of an airline pilot and a county library clerk. Some publications have his place of birth as Fremont, California while others name the smaller Castro Valley, California. He is of half Swedish descent. Hertzfeldt attended Mission San Jose High School in Fremont. In his childhood, Hertzfeldt drew homemade comic books and at the age of 15, he began to teach himself animation with a VHS video camera. Two of Hertzfeldt's teenage VHS cartoons can be seen on the "Bitter Films: Volume 1" DVD collection.

The sequence depicts Homer accidentally using a time-traveling remote control that regresses him to his original 1987 character model, then propels him into a distant Future incarnation of the show called The Sampsans where he and his family have evolved into grotesque, mindless, catchphrase-spouting creatures. Future Homer sadly remembers past Futuristic episodes, in which he still had an emotional connection with Marge and the children. Simpsons Producer Al Jean called it "crazier than we thought," and "the most insane one we've ever done."

Hertzfeldt prefers not to sell his animation artwork. In the late 1990s and early 2000s, his website Bitter Films annually auctioned off artwork instead to raise thousands of dollars for local Santa Barbara charities. Other original drawings have been occasionally given away through the Bitter Films online store through special promotions. Because Hertzfeldt also rarely does signings, his artwork is rare for animation Collectors and fans to own.

The special features for Don Hertzfeldt Volume One: 1995–2005 included a time-lapse documentary of the making of The Meaning of Life called "Watching Grass Grow", The Animation Show Trilogy cartoons, Lily and Jim deleted dialogues and outtakes, Rejected trivia captions, The Meaning of Life special effects audio commentary, an over 140-page "archive" section (of rare footage from Hertzfeldt's earliest cartoons, original pencil tests, deleted sequences, abandoned footage, and Sketch to scene comparisons), Lily and Jim audio commentary, Rejected audio commentary, and a retrospective booklet, with liner notes by Hertzfeldt

His first dialogue short, Lily and Jim, was released in 1997, and tells the story of a disastrous blind date. Its partially improvised vocal performances helped the short win twenty five awards, including the Grand Prize at the New Orleans Film Festival.

Hertzfeldt has never held a job other than creating his animated films. His earliest teenage video animations found film festival exposure, and in film school at the University of California, Santa Barbara he was able to find international distribution for each of his 16mm student films. He is a 1998 graduate with a B.A. in Film Studies.

In 1999, at the age of 22, Hertzfeldt was nominated for the Short Film Palme d'Or at the Cannes Film Festival for Billy's Balloon, where he was the youngest Director in competition. The same year Billy's Balloon won the Slamdance Film Festival Grand Jury Award.

In 2000, at the age of 23, Hertzfeldt was nominated for the Academy Award for Animated Short Film for his fifth short film, Rejected. He lost to Michaël Dudok de Wit for Father and Daughter.

Bitter Films' first DVD release was a 2001 limited edition DVD "single" of the short Rejected. The DVD included a deleted scene, audio commentary, and a few hidden pages. It is now out of print.

In 2002, Hertzfeldt joined the Academy of Motion Picture Arts and Sciences

In 2003, Hertzfeldt created The Animation Show with Beavis and Butt-head creator Mike Judge. It was a biennial North American touring festival that brought independent animated short films to more movie theaters than any distributor in history. The programs were personally curated by Hertzfeldt and Judge. A second Animation Show edition toured throughout 2005, featuring Hertzfeldt's short film The Meaning of Life and new films by animators like Peter Cornwell and Georges Schwizgebel. The third season of The Animation Show began its nationwide release in January 2007, featuring new work by animators Joanna Quinn and Bill Plympton, as well as Hertzfeldt's own Everything Will Be OK.

Almost four years in the making, Hertzfeldt's twelve-minute The Meaning of Life premiered at the 2005 Sundance Film Festival and toured film and animation festivals in 2005–2006. Though its abstract nature puzzled some critics, it received mostly positive reviews. The Atlanta Journal-Constitution called the film "the closest thing on film yet to Kubrick's 2001: A Space Odyssey."

Don Hertzfeldt Volume 2: 2006–2011, a DVD collection of all work from 2006–2011 (including the feature film version of It's Such a Beautiful Day) was released in November 2012. Special features for the release included over 40 minutes of live Q&A material from the touring program, the cartoon Wisdom Teeth, a deleted scene from It's Such a Beautiful Day, and a 24-page booklet. Advance pre-order customers for the release also received a 35 mm–film strip clipped from a release print of It's Such a Beautiful Day, and other free gifts.

In 2007, Everything Will Be OK was released as another DVD "single". Special features on this release included over a hundred pages of "archival" material (sketches, storyboards, deleted materials), and a hidden feature that played a narration-free version of the film.

In 2008, Comedy Central noted his work as having "influenced an entire generation of filmmakers."

In a March 2009 blog entry, Hertzfeldt compared filmmaking to his love of hiking and exploring new places: something he does just because he "enjoys doing it and will probably always enjoy doing it." He compared doing advertising to being paid to not go explore the woods, but to walk around someone's house eight hours a day wearing a sandwich board with a picture of a product on it. "Money's not the reason I take walks. It doesn't really factor into it. I take walks because I enjoy doing it. It's something I'd do if I was rich, and it's something I'd do if I were poor."

In April 2010, at the age of 33, Hertzfeldt received the San Francisco International Film Festival's "Persistence of Vision" Lifetime Achievement Award "for his unique contributions to film and animation," and "for challenging the boundaries of his craft."

The third and final chapter, It's Such a Beautiful Day, premiered at the 2011 Sundance Film Festival. Hertzfeldt traveled with It's Such a Beautiful Day in 2011 and 2012 on another North American theatrical tour to 30 cities.

In 2012, Hertzfeldt received the Ted M. Larson memorial award from the Fargo Film Festival, for his "contributions to film culture."

Hertzfeldt has had more films play in competition at the Sundance Film Festival than any other filmmaker, with eight: Rejected, The Meaning of Life, Everything Will Be OK, I Am So Proud of You, Wisdom Teeth, It's Such a Beautiful Day, World of Tomorrow, and World of Tomorrow Episode Two. He returned to the Sundance Film Festival in 2013 to serve on the Short Film Awards Jury.

In 2014, Hertzfeldt wrote, animated, and directed a surreal and Futuristic two-minute "couch gag" for the premiere episode of the 26th season of The Simpsons. It was the longest opening gag in the show's history and was described by Spin Magazine as "mind-melting," and "two of the strangest minutes of television ever to air on a major network during prime time."

From July to August 2015, Don Hertzfeldt ran a Kickstarter campaign to publish his films It's Such a Beautiful Day and The World of Tomorrow for the first time on Blu-ray, to help Finance Future productions. The campaign raised over $215,000. With rising pledges he remastered additional short films The Meaning of Life, Rejected, Billy's Balloon, Wisdom Teeth, and Lily and Jim and added them to the Blu-ray as well. Also included was an interview, a surprise film, and the first preview of a Future project. The disc run was limited, primarily available to Kickstarter supporters and fans who contacted Bitter Films directly.

In 2016, World of Tomorrow was nominated for the Academy Award for Animated Short Film at the 88th Academy Awards, Hertzfeldt's second nomination.

Hertzfeldt traveled with the film to theaters on a "winter mini-tour" in December 2017. The screenings opened with a surprise new two-minute cartoon, in which an animated Hertzfeldt introduces the program from the underground caverns of an alien planet.

In January 2018, the film played opening night at the Sundance Film Festival.

On finally making the leap to digital animation after twenty years of working with pencil and paper, Hertzfeldt joked, "I kind of feel like it’s like a rock band who traditionally was guitar, guitar, guitar and then for their new album, they’re like, we’re going electronic! But [then] they only use Casio keyboards and drum machines... It’s not the cutting edge CG we’re all used to."