The spoke about compassion, inner piece, evil and meditation during a session at the U.S. Conference of Mayors shown on Facebook Live.
"I'm one 81-year-old person with quite a lot of experiences. My experiences much bigger than your experiences," said the Dalai Lama. "You didn't know this, but I'm much older than you," joked Gaga. And they both laughed.
The singer is 30 years old.
Gaga asked questions chosen from social media and reporter Ann Curry helped serve as a moderator.
"How do you help young people address issues of poor self-esteem, managing eating disorders, addiction, self-harm and suicide?" one submission asked.
"These problems are a lack of ability [to have] compassionate feelings. Too much self-centered," the Dalai Lama replied, explaining today's culture is "too materialistic."
Another question for the the Tibetan dealt with evil: "How can I still feel at peace with so much horror in this wonderful world. I need peace of mind. I'm losing it."
He responded: "When some problem happens, if you look closely, it appears unbearable. The same problem, looked [at] from distance and wider perspective, then yes, 'there a problem I have to face,' but there are other very positive things ... so I should not feel a loss of hope."
Lady Gaga said humans must work together despite evil.
"As we're busy trying to figure out which group is causing the problem, evil is winning...we have to change the perspective," she said.
They both said they meditate.
"I am a poor practitioner of meditation. 81 years old... progress, not much," he said, smiling.
"You can judge my (young-looking) face," he said. "Nothing special medicine... My mind (is) always clear."
The Dalai Lama earlier was the keynote speaker, focusing his remarks on the global significance of building compassionate cities.
He spoke of self-created problems, giving examples of global warming, population increase and limited resources. He also said humans are too materialistic.
Presumptive Democratic presidential nominee Hillary Clinton also spoke to the group Sunday.