In 1986, Herschensohn unsuccessfully sought the Republican nomination for the United States Senate held by the liberal Democrat Alan Cranston. He finished second, with 587,842 votes (29.6 percent) to U.S. Representative Ed Zschau of the Silicon Valley, who received 7,347,384 (37.1 percent). In the general election, Cranston defeated Zschau to secure his fourth and final Senate term. Zschau, considered a moderate to liberal Republican later left the GOP and became an independent.

In 1992, when Cranston retired, Herschensohn won the Republican nomination by narrowly defeating U.S. Representative Tom Campbell, a liberal Republican who had been on the faculty of Stanford University. Herschensohn received 956,136 votes (38.2 percent) to Campbell's 895,970 (35.8 percent). The remaining 417,848 ballots (16.7 percent) went to Mayor Sonny Bono of Palm Springs. During the primary campaign and afterwards, Herschensohn became a close friend of Bono and encouraged his former rival to seek election to the United States House of Representatives in 1994. Bono was part of the freshman class in 1995 which brought a Republican majority to the U.S. House for the first time in forty years.

In the 1992 general election, Herschensohn, well-known as a Los Angeles area television commentator, was defeated by the Democrat, U.S. Representative Barbara Boxer. It is widely believed that the revelation just prior to the election that Herschensohn had attended a strip club undermined his prospects of victory. However, Herschensohn still ran ahead of U.S. President George H.W. Bush, who was badly beaten in the California balloting by Democrat Bill Clinton.