Pearce will join a list of stars including Kylie Minogue and Jason Donovan appearing in the show after absences of several decades to mark its final farewell.
The Australian actor is among the most successful of his many castmates, with roles in in films including LA Confidential, The King’s Speech and a recent appearance in TV’s award-winning The Mare of Easttown.
The very last episode of the show is set to air on August 1, bringing to a close Australia’s longest-running TV soap after 37 years.
Pearce told London newspaper Metro: “It is very exciting and surreal at the same time being back on set again, however it feels like coming home.
“It’s where it all started for me professionally. I’ve been asked to come back on occasions over the years and wondered if it was the right thing to do, but once I knew the show was finishing, I knew I had to do it.
“While I’ve caught up with many of the cast I worked with on the show over the years, there is nothing like being here all together again.”
Jason Herbison, Neighbours’ Executive Producer, said: “I’m incredibly honoured that Guy is returning to the show for a very special story arc.
“Having him back on set has been poignant for him and for us. He’s been very involved in the storyline, and I can’t wait to finally answer the question for viewers – who is Mike Young today?”
Pearce is just one of several Australian stars to get their big break on the Australian soap. Other names include Margot Robbie, Jesse Spencer, Alan Dale, Liam Hemsworth and Russell Crowe. Natalie Imbruglia went on to musical success, scoring two Brit Awards and three Grammy nominations.