McHale co-created Casualty's sister show alongside Mal Young, wrote the first ever episode which aired in 1999 and served as the programme's lead writer, before opting to take a break several years later. He then returned in 2006 as executive producer.
Speaking of his decision to stand down, he said: "I've had a terrific four years on Holby and am thrilled with what we've achieved. I'd like to thank cast, crew and production for all their hard work, talent and dedication. I know the show will go on from strength to strength."
Controller of drama at the BBC John Yorke said: "It's been a privilege to work with him, and we will all miss his extraordinary passion, vision and determination that Holby should be the best, most ambitious and most exciting show on BBC One."
He added in a message to staff: "It's worth pointing out that Tony was the first writer in the country ever entrusted with the status of showrunner on a big primetime drama, and it's to his immense credit that he has pulled it off with such success.
"Never out of the top ten, almost always in the top five and with a glorious BAFTA victory to his credit, we will all miss him hugely, and wish him the best of luck with future projects."
McHale's successor is due to be announced early in the New Year.
Prior to Holby City, McHale enjoyed a long stint as a writer and director on EastEnders.