Born into a prominent Philadelphia family, he was brother to Spencer Penrose, who in 1918 would build the elegant Broadmoor Hotel at Colorado Springs, Colorado. Boise Penrose graduated from Harvard with a law degree in 1881, and was accepted into the Pennsylvania bar association in 1883. He took an interest in politics and began working for Matthew Quay, a Pennsylvania political boss. He was elected to the Pennsylvania House of Representatives in 1884 and served until 1886 when he was elected to the State Senate, where he served as president pro tempore from 1889 to 1891.

Penrose stepped down from his position as a State Senator in 1897 to take office as a United State Senator. Penrose was a dominant member of the Senate Finance Committee and supported high protective tariffs. Penrose was elected the Republican leader of Pennsylvania upon Quay's death in 1904, and was reelected to this position in 1908. Penrose died in Washington, D.C. in 1921, and was buried in the Laurel Hill Cemetery in Philadelphia.

Senator Penrose was an avid outdoorsman and took pleasure in mountain exploration and big-game hunting. A mountain in Montana and another in the Dickson Range in the Bridge River Country in British Columbia were climbed and named by him. Local lore from the Bridge River Country told by his hunting guide, W.G. (Bill) Manson, was that the senator was a large man (overweight) and they had to shop all over the place to get a horse big enough to fit him and his custom saddle. The horse was so large no other saddle would fit him. The horse was called "Senator", and he was retired to the pasture because no standard saddle would fit him.