The network said on its website the radio call-in show will go off the air at the end of June and be replaced by "Here and Now," produced through a partnership between NPR and WBUR, Boston.
Conan, 63, has been the host of "Talk of the Nation" Monday-through-Thursday since 2001.
"Neal Conan, 'Talk of the Nation's' host, will depart after more than three decades with the network," NPR reported. "His past positions include stints as bureau chief in New York and London and as NPR's foreign editor, managing editor and news director."
Conan said in a statement he was "profoundly grateful for all the opportunities provided at NPR ... ."
He did not disclose what he planned to do next.
NPR is encouraging affiliate radio stations to replace "Talk" with an expanded version of "Here and Now," an afternoon news magazine-style program, The New York Times said.
NPR faces a $7 million budget deficit but Executive Vice President and Chief Content Officer Kinsey Wilson said in a statement the change was not motivated by spending constraints.
"NPR has been addressing the budget deficit in other ways, including cuts in travel and not filling empty jobs," Wilson said.
NPR is to begin distributing "Here and Now" this summer and Jeremy Hobson is to join Robin Young as its co-host, the Times said.