In 1962, he left the newspaper and became secretary of a Diet member, and in the 1969 general election, he was elected in the lower house at age 32. He was reelected 10 consecutive times. In 1980, he was involved in the Recruit scandal about receiving unlisted shares of Recruit (company) before they were publicly traded, and selling them after they were made public for a profit of approximately 1 million dollars. He was education minister in 1983 and 1984, international trade and industry minister in 1992 and 1993, and construction minister in 1995 and 1996.

In 1999, Mori began to assume control of the Mitsuzuka faction (formerly Abe faction) that had been headed by Hiroshi Mitsuzuka in the Liberal Democratic Party (LDP).

In November 2000, with Mori's approval ratings below 30%, opposition politicians attempted to win a vote of no confidence against Mori by soliciting support from rebels within the LDP. Hiromu Nonaka, the secretary general of the party, quashed the potential revolt by threatening to expel any LDP politicians who voted for the measure. The vote failed 237 to 190. Nonaka resigned days later amid speculation that he would challenge Mori for leadership of the LDP.

Mori appointed three cabinets. The third cabinet is officially referred to as a continuation of the second cabinet, as the changes came amid a major administrative realignment in January 2001 that eliminated several cabinet positions and renamed several key ministries.

In 2003 he received the highest distinction of the Scout Association of Japan, the Golden Pheasant Award.

He was awarded the Padma Bhushan, India's third highest civilian award, in 2004.

Mori became President of the Japan Rugby Football Union in June 2005. It had been hoped his clout would help secure the 2011 Rugby Union World Cup for Japan, but instead the event was awarded to New Zealand in late November 2005. This led Mori to accuse the Commonwealth of Nations countries of "passing the ball around their friends." Mori later assisted in Japan's successful bids for both the 2019 Rugby World Cup and 2020 Summer Olympics.

Mori remained an important player in Russo-Japanese relations following his resignation as prime minister due to his close personal relationship with Vladimir Putin. Prime Minister Yoshihiko Noda of the Democratic Party of Japan considered tapping Mori in 2012 to resolve the dispute between the two countries over the Kuril Islands, despite the fact that Noda and Mori were from opposing parties in the Diet. In 2013, Mori met with Putin and Sergey Naryshkin in preparations for a summit between Putin and Japanese Prime Minister Shinzō Abe. Mori had at one time suggested that Japan could give Russia three of the four disputed islands in exchange for a peace treaty, which went against the Japanese government's official view that Moscow should acknowledge Japan's ownership of all four.

In 2014, at the age of 76, he was appointed to head the organizing committee for the 2020 Summer Olympics in Tokyo. He quipped, "I am destined to live five or six more years if I am lucky. This will be my one last Service to the country." However, Mori drew international and domestic criticism for his critical statements about Japan's Olympic figure skaters Mao Asada and Chris Reed and Cathy Reed, who were representing Japan at the 2014 Sochi Olympics.