[3] He has been labelled "pro-Western" by contemporary historians, but was nevertheless harshly critical of Christianity as both false and heretical compared to Japanese Buddhism.

[4] In 1862, Matsudaira was unexpectedly made acting prime minister of the Tokugawa administration (seiji sōsai) in a move calculated to obtain imperial approval for the Shōgun's actions in signing unequal treaties (similar to those signed by Qing dynasty China) with the western powers in 1858, ending the national seclusion policy which was supported by the Imperial Court, and Yokoi accompanied him to Edo.

He also called for the complete opening of Japan to foreign trade, economic reform, and establishment of a modern military along western lines.

After reading Chinese scholar and reformer Wei Yuan's Illustrated Treatise on the Maritime Kingdoms, Yokoi became convinced that Japan should embark on a "cautious, gradual and realistic opening of its borders to the Western world" and thereby avoid the mistake China had made in engaging in the First Opium War.

Outraged and astounded by these radical ideas, conservatives within the government quickly stripped Yokoi of his posts, and even his samurai status, and placed him under house arrest in Kumamoto.