Darius Mills was born in North Salem, New York, and his early career was as a bank clerk and retailer. He joined the California Gold Rush in December 1848, and founded a bank in Sacramento. He never invested in gold mining or silver mining directly, as he considered mining to be too speculative. He rather started ancillary businesses that supported the mining industry, such as banks and railroads. He was a part owner of the Virginia and Truckee Railroad, which was the only link from the Comstock Lode to the Central Pacific Railroad. The major share holder in the railroad was William Sharon, whom WIlliam Ralston had sent to Virginia City as representative of the Bank of California. In 1864, with other investors, he founded the Bank of California, which grew large in the 1860s and 1870s, but collapsed due to financial irregularities involving its chief cashier, William Chapman Ralston. Mills used his personal fortune to revive the bank, along with Sharon, and attract new investment, and within three years, the bank was again strong. In 1854, he married Jane Templeton Cunningham with whom he had a son, Ogden and a daughter, Elisabeth, who married Ambassador Whitelaw Reid.

Darius Mills bought part of Rancho Buri Buri and built an estate named Millbrae, which gave its name to the present town that grew up around it. The 150 acres (0.6 km2) of the original estate bordering San Francisco Bay were leased by his grandson Ogden L. Mills to be used for Mills Field, now known as San Francisco International Airport. Later in life, Mills retired from banking, and returned to New York, where he participated in the development of a number of buildings in Manhattan, including 160 Bleecker Street, or “Mills House No. 1”. His devotion to philanthropy involved sitting on the boards of a number of charitable and cultural institutions. He died of a heart attack in 1910 at his Millbrae home, leaving an estate worth $36,227,391. His remains were returned to the East Coast for burial in the Sleepy Hollow Cemetery in Sleepy Hollow, New York. A number of local institutions are named for him, include Isabella I of Castileg Mills Hospital, the Mills Estate housing subdivision, San Francisco’s Mills Building, and Mills High School. The city of Millbrae, California, is also named after him, as well. The California State Capitol rotunda houses a statue donated by Mills that depicts Queen Isabella financing Christopher Columbus’s initial voyage. The San Francisco airport, was formerly names Mills Field, after him.