The news comes off the back of major speculation over his future with Leinster, with his contract expiring at the end of the current season. He is not on an Irish Rugby Football Union (IRFU) central contract, though, unlike recent re-signings Dan Sheehan, Josh van der Flier and Jamison Gibson-Park.
It also follows reports from the42 linking him with a move to Japan Rugby League One outfit Tokyo Suntory Sungoliath for next season, which could also impact his World Cup hopes with Ireland.
In a statement posted on social media, Leinster said: "We can confirm that James Lowe will depart from Leinster at the end of the season.
"With 71 tries in 101 appearances, he leaves as our record try-scorer and a true-blue legend.
"Let's give Lowey the send off he deserves at the URC Grand Final!
"Thank you for everything."
Lowe arrived in the Irish capital in 2017, and has since gone on to make 101 appearances at the time of writing. In that time, he has also scored 71 tries, the most of any player in the province's history, and helped them win one Champions Cup and five league titles.
His form in the famous blue jersey saw him drafted into the Ireland Test side, winning 45 Test caps after his debut in 2020 and representing the Emerald Isle during the 2023 World Cup. He also earned a spot in the British and Irish Lions touring squad last year, starting in two Tests against the Wallabies in the series victory.
Lowe's final appearance in Leinster colours will come in next Friday's United Rugby Championship (URC) final at Croke Park, in which they take on the Bulls in a repeat of last year's showpiece game.