The Tibetan spiritual leader will be the guest of honour at an event in Ebrington on 18 April, organised by the charity Children in Crossfire.
He will speak about the importance of compassion.
The Dalai Lama is a close friend of the charity's director Richard Moore, who was blinded by a rubber bullet as a child during the Troubles and later met the man who shot him.
He has described Mr Moore as "my hero".
"I often have to pinch myself when I realise the special relationship that I have with his Holiness and how lucky I am and how lucky Children in Crossfire is to have his Holiness as a patron," he said.
Welcoming the news that the Dalai Lama will be returning to Derry after six years, Mr Moore said: "We are thrilled to welcome His Holiness back to Derry/Londonderry.
"He came to the city six years ago as part of our 10th Anniversary celebrations and has been a dedicated patron of the charity since that time.
"We are delighted that people from across Northern Ireland and beyond will have an opportunity to see and hear him speak during this City of Culture year.
"It's particularly poignant that he is coming this time, when the eyes of the world will be on Derry because of UK City of Culture," he told UTV.
"It sends out a strong message from Derry to the rest of the world that we're not only celebrating art, we're not only celebrating music, which is very important- but we're also celebrating the real sense of compassion that people not only in Derry but throughout the whole of Northern Ireland that we have for others."
Children in Crossfire is a local charity which promotes childhood care and development in some of the poorest countries in the world.
It said other guests for the 'Culture of Compassion' event will be announced soon.
Tickets go on sale on Wednesday at Derry's Millennium Forum.