The broadcaster has spent more than three decades hosting the 9.30am - midday weekday show, and has been on BBC radio for 45 years altogether.
Explaining "it's time for a change", Bruce added: "I would stress that this is entirely my decision."
The 71-year-old will host a new mid-morning show on the Bauer radio station between 10am and 1pm from April.
In his announcement on Tuesday morning, he said: "Nothing stays the same forever and I have decided the time is right for me to move on from Radio 2 when I reach the end of my current contract in March.
"It’s been a tremendously happy time for me: I’ve made many friends and worked with many wonderful colleagues. However I feel that after 45 years of full-time broadcasting on BBC Radio it’s time for a change.
"I would stress that this is entirely my decision but some new opportunities have come up and I would like to continue my career in a slightly different way in the next few years, the details of which will be revealed shortly."
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Bruce added: "I will always be very proud of my association with the BBC and Radio 2 in particular and I’d like to thank everyone who has helped to make the mid-morning show a success."
Lorna Clarke, director of BBC Music, said: "Ken is an extraordinary broadcaster with an exceptional career over many decades. He has been part of every significant occasion marked by BBC Radio 2 and we, his faithful audience and the Radio 2 all-star line-up will miss his warm humour and wit.
"Congratulations on a brilliant career."
A replacement for Bruce and details of the new mid-morning show will be announced at a later date.
Bruce joined BBC Radio Scotland in 1977 and his first regular slot on Radio 2 was the Saturday Late Show in 1984.
The following year he fronted the Radio 2 Breakfast Show, taking over from Terry Wogan, and he moved to mid mornings in 1986. After a brief stint on late nights and early mornings, he returned to mid mornings in January 1992.
His other BBC work has included Radio 2's coverage of Eurovision since 1988, and he has been a regular presenter of Sunday Night is Music Night.