Betty Blake was born on September 9, 1879, at Silver Springs, later called Monte Ne (Benton County), to James Wyeth Blake, a miller, and Amelia Crowder Blake. Her father died when she was young, and the family moved a few miles north to Rogers (Benton County). Betty was seventh in a family of nine, and her mother supported the large family through dressmaking. Blake was a popular young lady who enjoyed performing in amateur theatrical performances.

In 1900, she met Will Rogers at her sister's home in Oologah, Indian Territory (now Oklahoma). The young couple's shared sense of humor and love of music fostered a friendship that survived long separations. The pair corresponded regularly but saw each other only occasionally. While he traveled and made a name for himself in show business, she clerked at the H. L. Stroud Mercantile Company and set type at the Rogers Democrat.

In 1906, Will proposed, but Blake, doubtful about a life in show business, refused him. A year and a half later, he proposed again, this time promising that they could settle down on a ranch in Oklahoma after a final tour. The couple married on November 25, 1908, in a simple ceremony at her family home.

The couple honeymooned in New York, where he was performing. She soon reconsidered her opposition to show business, and as offers of better jobs came his way, she encouraged him in his chosen career. They traveled together until their first child was born in 1911. Afterward, she returned to Rogers for long visits, and their second child was born there. Two more children followed, but one died at age two.

The family moved to California and bought a ranch in the Santa Monica hills in 1919 as his film career began to flourish. His popularity continued to grow, and frequent tours kept him on the road. Rogers remained focused on her home and family. Though far away, she kept her ties to her hometown, and she and her husband regularly contributed to charities in Rogers.

On August 15, 1935, Rogers's husband, along with aviator Wiley Post, died in a plane crash in Alaska. After his death, she concentrated on furthering his reputation. She contributed to the creation of the Will Rogers State Park at the Santa Monica ranch and the Will Rogers Memorial in Claremore, Oklahoma. She also wrote Will Rogers: His Wife's Story, published in 1941.

Betty Blake Rogers died of cancer on June 21, 1944, in Santa Monica and was buried in Claremore next to her husband.