By 1867 the ranch belonged to Alexander Grogan, an Irishman who settled in San Francisco and speculated in real estate and commodities. Grogan ran a dairy operation on the ranch from the 1860s until the late 1800s. He built many of the oldest buildings which stand on the ranch today including the Grogan house (1880s), the two large barns (1880s) and the Cheese House (1860s). Grogan died in 1886, and for the next 20 years the ranch was owned by his sister and two other owners.

In 1906, the ranch was purchased by Kingsley Macomber and George Sykes. Sykes took the land across highway 25 from the current location of the ranch, and Macomber took what is today the Paicines Ranch. During his ownership, many structures of Moorish design were built on the ranch, including stables, a water tank, a garage, and a new residence. Macomber raised horses on the ranch in addition to a large short horn cattle operation

In 1927 Macomber sold the ranch to Walter Murphy, a wealthy industrialist from Chicago and a friend of the Roosevelts. Eleanor Roosevelt was a guest at the ranch, and their son, Jimmy Roosevelt spent a year at the ranch recuperating from an illness. The Paicines Ranch was Murphy's 7th residence.

When Murphy died in 1943, Bob and Katherine Law purchased the ranch. In 1952 Judy Garland married Sid Luft in the Grogan House. During the 1960's the ranch was part of the world's largest varietal vineyard, planted by Mirassou Vineyards. The Law family owned the ranch until 1989 when it was purchased by Ridgemark Corporation, with the intention of developing a resort hotel, golf courses and single-family houses.

In 2001, as it became apparent that the development would not move forward, the ranch was purchased by Sallie Calhoun and Matt Christiano. Most of the historical buildings have been restored and are used either for ranch operations or as part of the ranch's unique event center. The ranch is managed to preserve and enhance both the built and natural environments for generations to come.