Awarded annually, the Praemium Imperiale recognises artists who have made a "major international impact" in the fields of architecture, sculpture, music, painting and theatre or film.
Williams and Tsien are best known for projects such as the Neurosciences Institute in California, The Barnes Foundation in Philadelphia, and the Lefrak Centre in Brooklyn.
The pair began working together in 1977, founding their practice Tod Williams Billie Tsien Architects in New York in 1986.
"The couple and their studio design buildings that blend seamlessly into their surroundings, have strong evidence of the hands from which they're made, and prioritise the experience of the lives lived within them," said the Japan Art Association.
"Throughout their body of work, no matter the complexity, they retain the values of their practice and endeavour to leave good marks upon the earth."
This is the 31st year of the Praemium Imperiale awards. Previous architecture laureates include Norman Foster, Rem Koolhaas, Jacques Herzog and Pierre de Meuron, Peter Zumthor, Zaha Hadid, Steven Holl and David Chipperfield.
Last year the prize went to French architect Christian de Portzamparc.
The Japan Art Association set up the prize, which awards each recipient 15 million yen (£100,000), in order to recognise the fields of contribution to humanity that go unrecognised by the Nobel Prizes.
"This year's laureates of the Praemium Imperiale have all made a significant contribution to our civilisation," said Chris Patten, former governor of Hong Kong and international advisor of Praemium Imperiale.
In 2018 Tsien called for better child care provision in the US, calling it the "biggest issue of inequality for women in the profession" [of architecture].
"It should be a federal issue," Tsien told Dezeen.
"The only way that you can keep working in a profession as demanding as architecture, is if you make a space for people with families," she continued.
Tod Williams Billie Tsien Architects won the competition to design the Obama Presidential Centre in Chicago, which is due to complete in the US city in 2022.
Williams and Tsien are joined as winners for the 2019 Praemium Imperiale by British-Palestinian sculptor Mona Hatoum and German violinist Anne-Sophie Mutter.
The other winners were South African painter William Kentridge, and Japanese kabuki theatre actor Bando Tamasaburo.
Main photo is by Taylor Jewell.