The comedy, which focused on the lives of the Harper family, has run since September 2000 and will conclude with its 11th series this spring.
BBC One boss Danny Cohen revealed the news in a statement, adding that the time is right to end the show as the children of Ben (Robert Lindsay) and Susan (Zoe Wanamaker) have left home.
"Now they have fled the nest we feel it's time to make room for new comedies," he said. "The 11th series, coming to BBC One later this year, will be the last."
Cheryl Taylor, the corporation's controller of Comedy Commissioning, said: "In Robert Lindsay and Zoe Wanamaker we are proud to have had two of Britain's finest comic actors in what has been a brilliantly successful and long-serving feature of the BBC One schedule.
"Now that almost a generation of British children have grown up with the Harper brood, played over the years by Kris Marshall, Daniela Denby-Ashe and Gabriel Thompson, we're looking to the future with new families and new comedies that we hope will prove equally popular."
She added: "We look forward to both Zoe and Robert continuing to be part of our BBC One Comedy family in the years to come, and would like to thank them and everyone involved in the production of My Family for their much valued contribution over the course of more than 100 episodes."
The tenth series, which saw the Harper's youngest son Michael come out as gay, premiered to just over 4m viewers last year.