"It is with heartbreak that executive producers David Milch and Michael Mann together with HBO have decided to cease all future production on the series 'Luck'," HBO said in a statement.
"While we maintained the highest safety standards possible, accidents unfortunately happen and it is impossible to guarantee they won't in the future. Accordingly, we have reached this difficult decision," HBO added.
"Luck", starring Dustin Hoffman and Nick Nolte, began airing in January. But two horses had already died after being injured in races filmed last year for the first season of the drama.
A third died earlier this week during filming for the second season. The American Humane Association, whose representatives were at the scene, said the horse had just passed a veterinarian's inspection and was being walked back to its barn when it reared, fell backward and was seriously injured. The horse was euthanised.
The American Humane Association said Tuesday's death was an accident "that was in no way a result of any mistreatment or negligence on the part of HBO."
It said HBO had been "extremely collaborative and responsive" to the Association's animal guidelines during filming.
"Luck" is the story of colorful characters involved in the world of horse-racing, gambling and training, and much of the show was filmed on location at the Santa Anita Racetrack in southern California.
Hoffman's role as a crime boss who buys a promising Irish racehorse was seen by critics as a tour de force that was likely to bring Emmy nominations for the 74-year-old Oscar-winning actor of movies "Rain Man" and "Kramer vs. Kramer".
But the complex, slow-burning drama was not a huge hit with audiences. Its January premiere attracted less than a million viewers.
HBO said on Wednesday it had maintained higher safety standards during production of "Luck" than exist in horse-racing anywhere "with many fewer incidents than occur in racing or than befall horses normally in barns at night or pastures."
"We are immensely proud of this series, the writing, the acting, the filmmaking, the celebration of the culture of horses, and everyone involved in its creation," the network said.
Executive producers Mann and Milch said in a joint statement: "The two of us loved this series, loved the cast, crew and writers. This has been a tremendous collaboration and one that we plan to continue in the future."
Two more episodes of the first season remain to air. It was not immediately clear if any of the second season episodes already filmed would be broadcast.
