The actor has said it is “the right time” to hang up his stethoscope after 18 years as Dr Martin Ellingham, the bad-tempered but well-loved GP.
Filming of the 10th series begins this week in the Cornish fishing village of Port Isaac.
The final eight episodes and a Christmas special will air on ITV later this year, it has been announced.
Clunes, 60, said: “I have loved going to Cornwall to make Doc Martin over the last 18 years, and I have looked forward to returning to this beautiful county this year for the tenth and final series.
“The people of Cornwall, and Port Isaac in particular, have always been so helpful to us when we are making the series.
“We have some great storylines for the new series, and for the Christmas special, which I hope Doc Martin fans will love.
“I shall miss Cornwall, and all the lovely people we have worked with. But it is the right time to say farewell to the Doc, and Portwenn.”
In the new series, the Doc makes an attempt to overcome his phobia of blood and he welcomes a baby daughter, Mary Elizabeth.
The series will feature the return of Dame Eileen Atkins as Aunt Ruth and Caroline Catz as Louisa, the love interest and eventual wife of Doc Martin.
Created by screenwriter Dominic Minghella and set in the Cornish hamlet of Portwenn, Doc Martin first aired in 2004.
ITV’s head of drama, Polly Hill, added: “If this really has to be the final series of Doc Martin, we thought we’d also commission a Christmas special.
“It’ll be sad to see the series come to an end after entertaining audiences on ITV for the last 18 years, but we’ll make sure the finale is memorable and befitting such a success story.”
Production company Buffalo Pictures have also announced they are making a documentary provisionally titled Doc Martin – A Celebration, giving fans a glimpse behind the scenes of the final series.
The series is produced by Clunes’ wife Philippa Braithwaite, whom he married in 1997.