Mrs. Obama was making her first visit to St. Jude as first lady, following in the footsteps of Nancy Reagan, Barbara Bush and Hillary Rodham Clinton. She chatted with the patients in an activity room and participated in a question and answer session.
The first lady's plane was delayed by about 1 1/2 hours due to a maintenance issue, but the children patiently waited for her, working on an art project.
St. Jude is considered a leading researcher of cancer and other life-threatening diseases that affect children. The hospital says it is working to increase the overall survival rate for childhood cancer to 90 per cent in the next decade.
Families never receive a bill from St. Jude for treatment, travel, housing and food. Celebrities pass through the hospital on a regular basis to meet with patients.
Mrs. Obama said she was invited to St. Jude by actress Marlo Thomas, whose father, actor Danny Thomas, founded St. Jude.
The first lady sat at tables with the children, some of whom had shaved heads. She asked them how they were feeling, if they were being treated well at the hospital and if they liked sports.
She then took a seat at the front of the room and took questions from the curious kids, such as what is the best place she has visited: "That's hard. I enjoyed meeting the Pope, visiting the Vatican"; what is her favourite sports team: "I love all of the Chicago teams"; and who is her favourite musical artist: "Everybody on the planet probably knows that Stevie Wonder is my favourite artist."
One patient asked if she would take "selfies" with them.
"I don't like selfies, but I'm going to do selfies for you guys," she said. The children took pictures with her after the Q&A session.
Mrs. Obama said it felt special for her to be able to meet with the kids at St. Jude.
"Sometimes, living in the White House, and being married to the president, and trying to live a life like that, it can be hard," she said. "But when I meet you guys, I am so inspired ... You all are smart and you're focused and you're just so courageous."