Following Treme, Simon wrote the HBO mini-series Show Me a Hero with journalist William F. Zorzi, a colleague at The Baltimore Sun and on The Wire.

[18] Simon was hired by the Baltimore Sun for a piece he wrote about Lefty Driesell, who was then the men's basketball coach at the University of Maryland.

Driesell had been extremely frustrated that one of his players was suspended from playing for sexual impropriety and called the victim, threatening to destroy her reputation if she did not withdraw her complaint.

[19] Simon says that he was initially altruistic and was inspired to enter journalism by The Washington Post's coverage of Watergate but became increasingly pragmatic as he gained experience.

"I felt Homicide the book and The Corner were not traditional journalism in the sense of coming from some artificially omniscient, objective point of view," said Simon.

[19][27] The episode was based on a story by executive producer Tom Fontana and featured Robin Williams in a guest starring role that garnered the actor an Emmy nomination.

Simon left his job with the Baltimore Sun in 1995 to work full-time on Homicide: Life on the Street during the production of the show's fourth season.

[35] He provided the story for the seventh season episodes "Shades of Gray" (with Julie Martin),[36] "The Same Coin" (again with Yoshimura)[37] and "Self Defense" (with Eric Overmyer).

[19] In 1997 he co-authored, with Ed Burns, The Corner: A Year in the Life of an Inner-City Neighborhood, the true account of a West Baltimore community dominated by a heavy drug market.

He said he "was less enamored of the braggadocio, all that big, we're-really-having-an-impact talk" and no longer believed that they were making a difference; he left his job at The Sun within a year for work on NBC's Homicide.

Originally they set out to create a police drama loosely based on Burns' experiences when working on protracted investigations of violent drug dealers using surveillance technology.

Owing to its reputation for exploring new areas, HBO was initially dubious about including a cop drama in their lineup, but eventually agreed to produce the pilot[52][53] after ordering a further two scripts to see how the series would progress.

"[55] For the fourth season Simon again turned to Burns' experience, this time his second career as a Baltimore public school teacher in examining the theme of education.

The two writers have much in common including a childhood in Silver Spring, attendance at the University of Maryland and their interest in the "fate of the American city and the black urban poor.

[63] Pelecanos left the production staff following the third season to focus on his next novel; Simon has commented that he missed having him working on the show full-time but was pleased that he continued to write for them and was a fan of the resultant book The Night Gardener.

[64] Simon has said that he was impressed with Overmyer's writing particularly in synthesizing the story for "Margin of Error" as the episode is the height of the show's political storyline but must also progress other plot threads.

[64] Simon and his writing staff were nominated for the Writers Guild of America Award for Best Dramatic Series at the February 2009 ceremony for their work on the fifth season.

[54] Overmyer lives part-time in New Orleans, and Simon believed his experience would be valuable in navigating the "ornate oral tradition" of the city's stories.

[70] Simon stated that the series would explore beyond the music scene to encompass political corruption, the public housing controversy, the criminal-justice system, clashes between police and Mardi Gras Indians, and the struggle to regain the tourism industry after the storm.

[73] In 2014, HBO greenlit production for Simon's next project Show Me a Hero, a six-hour miniseries co-written with William F. Zorzi and the episodes directed by Academy Award-winner Paul Haggis.

The miniseries is an adaptation of the nonfiction book of the same name by Lisa Belkin and tells the story of Nick Wasicsko, the youngest big-city mayor in the country who is thrust into racial controversy when a federal court orders to build a small number of low-income housing units in the white neighborhoods of Yonkers, New York.

[74] Oscar Isaac stars as Wasicsko and leads a cast, which includes Catherine Keener, Jim Belushi, Bob Balaban and Winona Ryder.

Themes explored include the rise of HIV, the violence of the drug epidemic and the resulting real estate booms and busts that coincided with the change.

An adaptation of Philip Roth's novel, The Plot Against America is an alternate history told through the eyes of a working-class Jewish family in Newark, New Jersey; as they watch the political rise of Charles Lindbergh, an aviator-hero and xenophobic populist, who becomes president and turns the nation toward fascism.

[97] When asked about these comments, Simon said that he had spoken with "some hyperbole and, I hope, comic effect", adding that his basic viewpoint was: "that simple revenge is both empty and beside the point and that a good story carefully told has to speak to larger themes.

[100] In 2013, Simon compared the global surveillance disclosures uncovered by Edward Snowden to a 1980s effort by the City of Baltimore to record the numbers dialed from all pay phones.

"[101][102] During a November 2013 speech at the Festival of Dangerous Ideas in Sydney, he said that America has become "a horror show" of savage inequality as a result of capitalism run amok, and that "unless we reverse course, the average human being is worthless on planet Earth.

"[105] During the 2016 Democratic presidential primaries, Simon praised Bernie Sanders for "rehabilitating and normalizing the term socialist back into American public life", but opposed some attacks against Hillary Clinton which he felt focused on her presumed motives rather than the substance of policies.

[100] In April 2022, David Simon thanked Russian opposition leader Alexei Navalny for using a quote from the TV series The Wire in his court speech and wished good luck to the politician.

[113] In 2019, Simon joined a host of other writers in firing their agents as part of the WGA's stand against the ATA after failing to come to an agreement on their "Code of Conduct".