He is the son of Ed Greaney, a presence at WMC-TV Memphis for over 50 years and the namesake for the station's current newsroom. Greaney has degrees in political science and international relations, which would later play a major part in his writing career. Mark continues to reside in Memphis, Tennessee along with his family.
Greaney previously worked as a waiter and bartender for ten years, then later in a surgical technology company, while working on two novels in his spare time. After finishing one of them, primarily about the aftermath of the Bosnian civil war, he gave the first 20 pages of his work to his favorite author Ralph Peters's agent, Scott Miller, in a book conference in September 2006. Miller liked the book but later did not go forward with it, saying that "it was unmarketable," according to Greaney. But he urged Greaney to write another one, which later would be The Gray Man. After finishing this novel, Miller agreed to represent him, and later found a publisher, Jove Books.
The national success of The Gray Man made Greaney quit his job in the medical devices company and make the transition to becoming a full-time writer. He was later given a three-book deal by his publisher in 2009. In addition, The Gray Man's success spawned an equally successful series, with five more sequels as of 2017: On Target (2010), Ballistic (2011), Dead Eye (2013), Back Blast (2016), and Gunmetal Gray (2017).
The Gray Man is currently being adapted into a motion picture by Sony Pictures and tied to director Christopher McQuarrie.
Greaney has been a fan of Tom Clancy for years, and has read all of his books, beginning with Patriot Games. So when Clancy was looking for a new co-author, Greaney found out that his editor at Berkley Books was also Clancy's editor at G. P. Putnam's Sons. His editor later referred to his agent, who asked Greaney to be Clancy's co-author. Commenting on the experience, Greaney recalled: "I wish I could say I was excited, but the truth is, I was terrified. After I caught my breath, I offered to 'try out' because there were some other authors also in the running. I wrote twenty-five pages, handed them in and soon thereafter, I was in Baltimore meeting with Tom Clancy." They later collaborated on Clancy's last three novels before his death in October 2013: Locked On (2012), Threat Vector (2013), and Command Authority (2013).
After Clancy's death, with the backing of his family and estate, Greaney continued the Jack Ryan and The Campus Universe left behind by Clancy, and has written four novels as of 2016: Tom Clancy: Support and Defend (2014), Tom Clancy: Full Force and Effect (2014), Tom Clancy: Commander in Chief (2015) and Tom Clancy: True Faith and Allegiance (2016). Regarding the publisher's decision to feature Clancy's name at the top in massive letters and having his name in smaller letters for the covers of the post-Clancy novels, Greaney commented: “It really feels like a humongous honor to do it. I get pretty good billing. The Tom Clancy name is one thing you can put on your book that will make it stand out from across the room.”
On February 19, 2017, Greaney announced that he will exit the Jack Ryan Universe franchise, as well as Grant Blackwood, Clancy's former co-author and frontrunner of the spin-off Jack Ryan, Jr. series of novels at that time. Replacing Greaney will be novelist Marc Cameron, previously known for his Jericho Quinn series of thrillers, while novelist Mike Maden, known for his Drone series of military thriller novels, will replace Blackwood.