The actress has landed the part of Kirsty, a lazy and wily agency nurse who is booked by new arrival Fletch (Alex Walkinshaw) after he meets her in a bar.
Speaking of her new part, Flanagan commented: "I'm really pleased to be working with the BBC in a show that I really enjoy."
Holby City's executive producer Oliver Kent added: "We are all hugely excited to have Helen on the show - she is a superstar soap actress and she is going to ruffle some feathers with Colette! It is definitely an episode to watch."
Flanagan, who is best known for playing Corrie's Rosie Webster between 2000 and 2012, will appear on Holby in July.
Since quitting the cobbles, the 23-year-old has appeared on a number of reality shows including ITV's I'm a Celebrity, Get Me Out Of Here! She has also shot some short film roles.
Holby City airs on Tuesdays at 8pm on BBC One.
Digital Spy Soap Scoop video - hit play below for gossip on Sarah's Coronation Street return, Kat's devastating decision in EastEnders, Laurel's problems exposed in Emmerdale and a turn to the dark side for Darren in Hollyoaks.