The cub was born at 6:35 p.m. Eastern Time, the zoo said in an Instagram post that announced the "joyous news." It will take some time before the sex of the cub can be determined.
"Mei Xiang picked the cub up immediately and began cradling and caring for it," the zoo said in a statement. "The panda team heard the cub vocalize."
Panda lovers around the world were able to see the birth on the zoo's Panda Cam. Zookeepers also were using the camera to keep an eye on mom and baby.
The cub is Mei Xiang's fourth. Her first three offspring, Tai Shan, Bao Bao and Bei Bei, were transported to China at age 4 under an agreement with the Chinese government.
"Giant pandas are an international symbol of endangered wildlife and hope, and with the birth of this precious cub we are thrilled to offer the world a much-needed moment of pure joy," said Steve Monfort, John and Adrienne Mars Director of the Smithsonian's National Zoo and Conservation Biology Institute. "Because Mei Xiang is of advanced maternal age, we knew the chances of her having a cub were slim. However, we wanted to give her one more opportunity to contribute to her species' survival."
At 22, Mei Xiang is the oldest giant panda to successfully give birth in the United States. The oldest in the world gave birth in China at age 23.
Mei Xiang gave birth in a small den, where she created a nest out of branches. Although the place looks tiny for a big panda, the zoo said giant pandas in wild give birth in small dens. "They stay in these dens for about the cub's first 100 days," the zoo said on Instagram.
Earlier this week, the zoo, part of the Smithsonian Institution, posted an image from Mei Xiang's ultrasound that confirmed the pregnancy. "Keep your paws crossed!" the zoo posted, reporting that the fetus was "kicking and swimming in the amniotic fluid."
"We need this! We totally need this joy," zoo spokeswoman Pamela Baker-Masson said earlier this week when the pregnancy was confirmed. "We are all in desperate need of these feel-goods."
Giant pandas at birth are about the size of a stick of butter. They're pink and hairless; the distinctive black and white fur markings of giant pandas come later.
The zoo said Mei was impregnated via artificial insemination, a process which was heavily affected by precautions over the COVID-19 pandemic. The procedure was conducted shortly after the entire zoo shut down on March 14. The zoo has since reopened on a limited basis.
The father is giant panda Tian Tian.
Rather than using a combination of stored frozen sperm and fresh semen, the zoo inseminated Mei Xiang only with thawed-out semen to minimize the number of close-quarters medical procedures. If successful, it would be the first of its kind in the U.S. using only frozen sperm.
Associated Press writer Ashfraf Khalil contributed to this report.