The Deuce tells the story of the legalization and ensuing rise of the porn industry in New York beginning in the 1970s and its ongoing rise through the mid-1980s. 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.

Simon was born in Washington, D.C., the son of Dorothy Simon (née Ligeti), a homemaker, and Bernard Simon, a former Journalist and then public relations Director for B'nai B'rith for 20 years. In March 1977, when Simon was still in high school, Simon's Father was one of a group of over 140 people held hostage (and later released) in Washington, D.C. by former national secretary of the Nation of Islam Hamaas Abdul Khaalis in the Hanafi Siege.

Upon leaving college, Simon worked as a police reporter at The Baltimore Sun from 1982 to 1995. He spent most of his career covering the crime beat. A colleague has said that Simon loved journalism and felt it was "God's work". 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. Later in his career he aimed to tell the best possible story without "cheating it".

Simon graduated from Bethesda-Chevy Chase High School in Bethesda, Maryland, and wrote for the school newspaper, The Tattler. In 1983, he graduated from the University of Maryland, College Park. While at college he wrote for The Diamondback and became friends with contemporary David Mills.

Simon was a union captain when the writing staff went on strike in 1987 over benefit cuts. He remained angry after the strike ended and began to feel uncomfortable in the writing room. He searched for a reason to justify a leave of absence and settled on the idea of writing a novel. "I got out of journalism because some sons of bitches bought my newspaper and it stopped being fun," says Simon.

Simon was raised in a Jewish family with roots that originated in Eastern Europe and Hungary (his maternal grandfather had changed his surname from "Leibowitz" to "Ligeti"). He has a brother, Gary Simon, and a sister, Linda Evans, who died in 1990.

In 1991, Simon was married to graphic Artist Kayle Tucker. They had a son, Ethan Simon. The marriage ended in divorce.

The book won the 1992 Edgar Award for Best Fact Crime book. The Associated Press called it "a true-crime classic". The Library Journal also highly recommended it, and Newsday described it as "one of the most engrossing police procedural mystery books ever written". Simon credits his time researching the book as altering his writing style and informing later work. He learned to be more patient in research and writing, and said a key lesson was not promoting himself but concentrating on his subjects. Simon told Baltimore's City Paper in 2003 that Homicide was not traditional journalism. "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. "They're immersed in the respective cultures that they cover in a way that traditional journalism often isn't."

The publishers of Homicide: A Year on the Killing Streets were eager for a screen adaptation and submitted it to numerous Directors but there was little interest. Simon suggested that they send the book to Baltimore native and film Director Barry Levinson. Levinson's assistant Gail Mutrux enjoyed the book and both she and Levinson became attached as producers. The project became the award-winning TV series Homicide: Life on the Street (1993–1999), on which Simon worked as a Writer and Producer.

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. Simon wrote the teleplay for the season four episodes "Justice: Part 2" and "Scene of the Crime" (with Anya Epstein). For season five he was the show's story Editor and continued to contribute teleplays writing the episodes "Bad Medicine" and "Wu's on First?" (again with Epstein). He was credited as a Producer on the show's sixth and seventh seasons. He wrote the teleplays for parts two and three of the sixth season premiere "Blood Ties" (the latter marking his third collaboration with Epstein) and provided the story for the later sixth season episodes "Full Court Press" and "Finnegan's Wake" (with James Yoshimura). He provided the story for the seventh season episodes "Shades of Gray" (with Julie Martin), "The Same Coin" (again with Yoshimura) and "Self Defense" (with Eric Overmyer). Simon wrote the story and teleplay for the seventh season episodes "The Twenty Percent Solution" and "Sideshow: Part 2". Simon, Martin and teleplay Writer T. J. English won the Humanitas Prize in the 60 minutes category for the episode "Shades of Gray". Simon was nominated for a second WGA Award for Best Writing in a Drama for his work on "Finnegan's Wake" with Yoshimura and Mills (who wrote the teleplay).

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. Simon credits his Editor John Sterling with the suggestion that he observe a single drug corner. He took a second leave of absence from the Baltimore Sun in 1993 to research the project. Simon became close to one of his subjects, drug addict Gary McCullough, and was devastated by his death while he was writing the project. Simon says that he approached the research with the abstract idea that his subjects may die because of their addictions but it was not possible to fully prepare for the reality. He remains grateful to his subjects saying "This involved people's whole lives, there's no privacy in it. That was an enormous gift which many, many people gave us. Even the most functional were at war with themselves. But they were not foolish people. And they made that choice."

Simon was reunited with his The Corner producers Robert F. Colesberry and Nina K. Noble on The Wire. Simon credits Colesberry for achieving the show's realistic visual feel because of his experience as a Director. They recruited Homicide star and Director Clark Johnson to helm the pilot episode. The completed pilot was given to HBO in November 2001. Johnson returned to direct the second episode when the show was picked up, and would direct the series finale as well, in addition to starring in the fifth season.

He was the creator, executive Producer, head Writer, and show Runner for all five seasons of the critically acclaimed HBO television series The Wire (2002–2008). He adapted the non-fiction book Generation Kill into a television mini-series, and served as the show Runner for the project. He was selected as one of the 2010 MacArthur Fellows and named an Utne Reader visionary in 2011. Simon also created the HBO series Treme with Eric Overmyer, which aired for four seasons. Following Treme, Simon wrote the HBO mini-series Show Me a Hero with Journalist william F. Zorzi, a colleague first at The Baltimore Sun, and again later on The Wire.

Simon produced and wrote Generation Kill for HBO with Ed Burns. They again worked with Nina Noble as a Producer. The miniseries is an adaption of the non-fiction book of the same name. It relates the first 40 days of the 2003 invasion of Iraq as experienced by 1st Reconnaissance Battalion and their embedded reporter, Evan Wright. Simon and Burns worked with Wright in adapting his book into the series.

In an interview in Reason in 2004, Simon said that since leaving the newspaper Business he has become more cynical about the power of journalism. "One of the sad things about contemporary journalism is that it actually matters very little. The world now is almost inured to the power of journalism. The best journalism would manage to outrage people. And people are less and less inclined to outrage," said Simon. "I've become increasingly cynical about the ability of daily journalism to effect any kind of meaningful change. I was pretty dubious about it when I was a Journalist, but now I think it's remarkably ineffectual." In 1988, disillusioned, Simon took a year's leave to go into the Baltimore Police Department Homicide Unit to write a book.

One of the actions Simon took was to name a character in The Wire after Marimow and make the character "a repellent police-department toady." Carroll left the Baltimore Sun to become Editor at the Los Angeles Times and resigned in 2005 after budget cuts were announced. "He stands up like a [bleeping] hero, takes a bullet," said Simon. In 2006 Marimow was diagnosed with prostate cancer, something that Simon said "took the edge off" his grudge. Carroll and Marimow "were fuel for 10 years of my life. ... And now, I got nothing," Simon said.

In a talk that Simon gave to a live audience in April, 2007 at the Creative Alliance's storytelling series, Simon disclosed that he had started writing for revenge against John Carroll and Bill Marimow, the two most senior editors at The Baltimore Sun when Simon was a reporter at the paper. Simon said he had watched Carroll and Marimow "single-handedly destroy" the newspaper and that he spent over ten years trying to get back at them.

In 2008, Simon married Baltimore Novelist and former Sun reporter Laura Lippman in a ceremony officiated by John Waters. They have a daughter named Georgia Ray Simon, who was born in 2010.

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. Simon and Burns collaborated to write the series finale "-30-" which received the show's second Emmy nomination, again in the category Outstanding Writing for a Drama Series.

Simon collaborated with Eric Overmyer again on Treme, a project about Musicians in post-Katrina New Orleans. 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. Simon also consulted with New Orleans natives Donald Harrison Jr., Kermit Ruffins, and Davis Rogan while developing the series. The show focuses on a working-class neighborhood, and is smaller in scope than The Wire. The series premiered on April 11, 2010 on HBO and ran for four seasons.

Simon was the 2012 commencement speaker for the Georgetown University College of Arts and Sciences, as well as the speaker for the Bethesda-Chevy Chase High School graduation.

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 worth less on planet Earth. Unless we take stock of the fact that maybe socialism and the socialist impulse has to be addressed again; it has to be married as it was married in the 1930s, the 1940s and even into the 1950s, to the engine that is capitalism."

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 nation who finds himself 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. Oscar Isaac stars as Wasicsko and leads a cast, which includes Catherine Keener, Jim Belushi, Bob Balaban and Winona Ryder. The miniseries premiered on August 16, 2015.

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.

The Deuce is a 1970s-1980s drama television series set and produced in and around the pornography industry in Times Square, New York. Created and written by Simon along with frequent collaborator George Pelecanos, the series pilot began shooting in October 2015. It was picked up to series in January 2016. It premiered on September 10, 2017 and is broadcast by the premium cable network HBO in the United States.