When William Rockhill Nelson died in 1915, his estate passed first to his wife and daughter, then to a trust for art acquisition. Around the same time, retired Kansas City schoolteacher Mary Atkins left her own bequest for a museum. Trustees of both estates decided to combine forces, pooling their resources with smaller bequests to create a single institution. Architects Wight and Wight broke ground in July 1930, and the classical Beaux-Arts building -- modeled on the Cleveland Museum of Art -- opened on December 11, 1933, at a final cost of $2.75 million (roughly $54 million in today's dollars). On its exterior, sculptor Charles Keck carved 23 limestone panels depicting the march of civilization from east to west, including wagon trains heading out from Westport Landing. Because Nelson donated money rather than a personal collection, curators built the holdings from scratch. The timing was extraordinary: at the height of the Great Depression, masterworks flooded the global market with few buyers. Within a short time, the Nelson-Atkins had assembled one of the largest art collections in the country.

The museum's celebrated Asian art collection owes its existence largely to one man. Laurence Sickman was a Harvard fellow living in China in the early 1930s when the Nelson-Atkins trustees began sending him thousands of dollars to buy art. His scholarly expertise cost them nothing -- he was on a scholarship. Sickman traveled 6,000 miles to attend the gallery's opening in December 1933, then returned to China to continue acquiring. By 1941 his purchases had given Kansas City one of the finest Asian collections in the United States, including one of the celebrated group of glazed pottery luohans from Yixian, dating to around 1000 AD. Sickman later served as a Monuments Man during World War II in England, India, and China. He became the museum's director and orchestrated the landmark 1975 exhibition of archaeological finds from the People's Republic of China, which attracted 280,000 visitors and made Kansas City one of only four cities -- after Paris, Toronto, and Washington -- on the exhibition's tour.

The collection ranges across millennia and continents. Egyptian pharaohs and Cycladic idols share space with sculptures from the Assyrian palace of Ashurnasirpal II at Nimrud. The European galleries hold works by Caravaggio, Rembrandt, El Greco, Monet, and Van Gogh. In 2016, forensic analysis of the underpainting of The Temptation of St. Anthony re-attributed the panel to Hieronymus Bosch himself, making it one of only 25 authenticated Bosch paintings in the world. The American gallery holds the largest public collection of works by Thomas Hart Benton, who lived in Kansas City. In 2023, the museum won a Thomas Eakins painting called Sailing in a wager with the Philadelphia Museum of Art after the Kansas City Chiefs defeated the Philadelphia Eagles in the Super Bowl. The Donald J. Hall Sculpture Park, designed by Dan Kiley, contains the largest collection of monumental Henry Moore bronzes in the United States, alongside works by Auguste Rodin, Alexander Calder, and George Segal.

In 2007, Time magazine ranked the museum's Bloch Building addition number one on its list of the ten best new architectural marvels worldwide. Designed by Steven Holl Architects, the addition consists of five translucent glass pavilions -- each 27 to 60 feet tall -- that emerge from the landscape like crystalline echoes of the original stone facade. Most exhibition space is below ground. Natural light filters through the glass lenses above, a decision that went against traditional conservatorial thinking. Officials said advances in glass technology allowed them to block ultraviolet rays while still illuminating the art with daylight. The Bloch Building houses the photography galleries, the contemporary collection, and the Noguchi Sculpture Court, the third-largest collection of Isamu Noguchi works outside of New York and Japan. A reflecting pool on the north side contains 34 oculi that funnel light into the parking garage below. The museum's seven entrances invite visitors to approach from any direction.

The museum has never charged admission. Hallmark Cards chairman Donald J. Hall Sr. donated the entire Hallmark Photographic Collection in 2006, spanning the history of photography from 1839 to the present, with works by Dorothea Lange, Alfred Stieglitz, Andy Warhol, and Cindy Sherman. The museum's 6,100-square-foot Native American galleries, opened in 2009, are among the largest such displays in any comprehensive art museum, with works ranging from ancient Mississippian culture to contemporary artists. The museum has also worked to research and, where appropriate, repatriate Nazi-era art to the descendants of its original owners. Among its most closely studied provenance cases is Les Boules de Neige by Pierre Bonnard, recovered from the Altaussee salt mine where the Nazis had stored looted art. The museum conducts this work openly, publishing its findings and collaborating with the American Alliance of Museums' Nazi-Era Provenance Internet Portal. From its Depression-era origins to its glass-walled future, the Nelson-Atkins remains what William Rockhill Nelson intended: a world-class collection, free and open to all.