The Boxer Uprising greatly affected Pearl and her family. Pearl's Chinese friends deserted her and her family, and Western visitors decreased too.

In 1911, Pearl left China to attend Randolph - Macon Woman's College in Virginia, US, graduating (Phi Beta Kappa) in 1914. From 1914 to 1933, she served as a Presbyterian missionary, but her views later became highly controversial in the Fundamentalist – Modernist Controversy, leading to her resignation.

In 1914, Pearl returned to China. She married an agricultural economist missionary, John Lossing Buck, on May 13, 1917, and they moved to Suzhou, Anhui Province, a small town on the Huai River (not be confused with the better known Suzhou in Jiangsu Province). It is this region she described later in The Good Earth and Sons.

From 1920 to 1933, Pearl and John made their home in Nanking (Nanjing), on the campus of Nanjing University, where both had teaching positions. Pearl taught English literature at the University of Nanjing and the Chinese National University. In 1920, the Bucks had a daughter, Carol, afflicted with phenylketonuria. In 1921, Pearl's mother died and shortly afterward her father moved in. In 1924, they left China for John's year of sabbatical and returned to the United States for a short time, during which Pearl earned her Masters degree from Cornell University. In 1925, the Bucks adopted Janice (later surnamed Walsh). That fall, they returned to China.

The tragedies and dislocations that Pearl suffered in the 1920s reached a climax in March 1927, during the "Nanking Incident". In a confused battle involving elements of Chiang Kai-shek's Nationalist troops, Communist forces, and assorted warlords, several Westerners were murdered. Since her father Absalom was a missionary, the family decided to stay in Nanjing until the battle reached the city. When violence broke out, a poor Chinese family allowed them to hide in their hut while the family house was looted. The family spent a day terrified and in hiding, after which they were rescued by American gunboats. They traveled to Shanghai and then sailed to Japan, where they stayed for a year. They later moved back to Nanjing, though conditions remained dangerously unsettled. In 1934, they left China permanently.

In 1935, the Bucks were divorced. Richard Walsh, president of the John Day Company and her publisher, became Pearl Buck's second husband. The couple lived in Pennsylvania.

During the Cultural Revolution Buck, as a preeminent American writer of Chinese peasant life, was denounced as an "American cultural imperialist." Buck was "heartbroken" when Madame Mao and high level Chinese officials prevented her from visiting China with Richard Nixon in 1972.

Pearl S. Buck died of lung cancer on March 6, 1973 in Danby, Vermont and was interred in Green Hills Farm in Perkasie, Pennsylvania. She designed her own tombstone. The grave marker is inscribed with Chinese characters representing the name Pearl Sydenstricker.

Buck was highly committed and passionate about a range of issues that were largely ignored by her generation; many of her life experiences and political views are described in her novels, short stories, fiction, children's stories, and the biographies of her parents entitled Fighting Angel (on Absalom) and The Exile (on Carrie). She wrote on a diverse variety of topics including women's rights, Asian cultures, immigration, adoption, missionary work, and war.

In 1949, outraged that existing adoption services considered Asian and mixed race children unadoptable, Pearl established Welcome House, Inc., the first international, interracial adoption agency. In nearly five decades of work, Welcome House has placed over five thousand children. In 1964, to support children who were not eligible for adoption, Buck established the Pearl S. Buck Foundation to "address poverty and discrimination faced by children in Asian countries." In 1965, she opened the Opportunity Center and Orphanage in South Korea, and later offices were opened in Thailand, the Philippines, and Vietnam. When establishing Opportunity House, Buck said, "The purpose... is to publicize and eliminate injustices and prejudices suffered by children, who, because of their birth, are not permitted to enjoy the educational, social, economic and civil privileges normally accorded to children."

In the late 1960s, Pearl toured West Virginia to raise money to preserve her family farm in Hillsboro, WV. Today The Pearl S. Buck Birthplace is a historic house museum and cultural center. She hoped the house would "belong to everyone who cares to go there," and serve as a "gateway to new thoughts and dreams and ways of life."

Long before it was considered fashionable or politically safe to do so, Buck challenged the American public on topics such as racism, sex discrimination and the plight of the thousands of babies born to Asian women left behind and unwanted wherever American soldiers were based in Asia. During her life Buck combined the multiple careers of wife, mother, author, editor and political activist.

Contemporary reviewers were positive, and praised her "beautiful prose," even though her "style is apt to degenerate into over repetition and confusion." Peter Conn, in his biography of Buck, argues that despite the accolades awarded her, Buck's contribution to literature has been mostly forgotten or deliberately ignored by America's cultural gatekeepers. Kang Liao argues that Buck played a "pioneering role in demythologizing China and the Chinese people in the American mind." Phyllis Bentley, in an overview of her work published in 1935, was altogether impressed: "But we may say at least that for the interest of her chosen material, the sustained high level of her technical skill, and the frequent universality of her conceptions, Mrs. Buck is entitled to take rank as a considerable artist. To read her novels is to gain not merely knowledge of China but wisdom about life."

Anchee Min, author of a fictionalized life of Buck, broke down upon reading Buck, because she had portrayed the Chinese peasants "with such love, affection and humanity"."

Buck was honored by the United States Postal Service with a 5¢ Great Americans series postage stamp.

(賽 珍珠故居) Pearl's former residence at Nanjing University is now the Nanjing University Science and Technology Industry Group Building along the West Wall of the university's north campus. U.S. President George H.W. Bush toured the Pearl S. Buck House in October 1998. He expressed that he, like millions of other Americans, had gained an appreciation for the Chinese through Pearl's works.