The Doc Martin star will play the title role, while Cold Feet's Fay Ripley, Butterflys actress Wendy Craig, Worst Week Of My Life star Geoffrey Whitehead, Game On's Neil Stuke and Moving Wallpaper's Lucy Liemann are also confirmed for the cast.
Simon Nye, who worked with Clunes of Men Behaving Badly, will write the script with original creator David Nobb. The six 30-minute episodes will air later this year.
"I am really excited about Reggie Perrin returning to our screens," said BBC One Controller Jay Hunt. "It feels as fresh and sharp now as it did all those years ago. It will be a vital part of our overall comedy offering on the channel."
The original show, which ran for three series between 1976 and 1979 and starred the late Leonard Rossiter, followed the story of sales executive Reggie Perrin, who found himself struggling with a mid-life crisis because of the monotony of his life, marriage and office job.
A follow-up series starring Geoffrey Palmer, The Legacy Of Reginald Perrin, ran for one series in 1996.