1850 found him studying in Hirato, Kyūshū, and in the following year he went on a study tour of Tōhoku. This latter was without the permission of the daimyō, a reckless and potentially dangerous act. He went on to study gunnery, and through the medium of Rangaku (lit. "Dutch Learning") Western Ideas. To deepen his knowledge of the West he tried to board a Russian ship which had docked at Nagasaki but was unsuccessful. This was in 1853: the following year saw the visit to Shimoda, Izu of the US Black Ship fleet led by Commodore Perry. Shōin succeeded in getting on board the flagship of the fleet but was not allowed to sail with it. Returning to land he surrendered himself to the Shogunate authorities and was imprisoned, first in Edo and then in Hagi. His imprisonment in Hagi was transmuted to a kind of house arrest and in 1856 he started giving lessons at a school an uncle of his had founded, the Shōka Sonjuku. His students there were mostly from low-ranking samurai families.  According to Umihara Tōru's  "Yoshida Shoin and Shoka Sonjuku The True Spirit of Education" Shōin taught at the school for just under three years, instructed a total of 92 students. and achieved astonishing results. Of the 92, two, Itō Hirobumi and Yamagata Aritomo, went on to become Prime Ministers, four served as cabinet ministers, and another four became prefectural governors or lieutenant governors. And the roll call does not stop there:  "If one adds the twelve diplomats, justices, high-ranking military officers, and technical experts who were given either imperial honour or court rank  the number of major success stories comes to twenty-two".

In 1858 the Shogunate gave way to the inevitable and signed peace and friendship treaties with the US, the UK, and Russia. However, the opening of ports to foreign trade mandated by the treaties met with violent opposition throughout the country and the government responded with the Ansei Purge ("Ansei-no-taigoku"), which saw over 100 prominent officials forced out of their posts. Opposition to the treaties  was driven by the  Sonnō jōi  ("Revere the Emperor, Expel the Barbarians") movement. This was a slogan which had first been expressed in China during the Spring and Autumn Period (春秋時代, 771 to 476 BC) and adapted to Japan's needs in the 18th Century by, among others, Motoori Norinaga. The key Japanese interpretation was that absolute loyalty was owed to the Emperor, and not to the Tokugawa Shogunate. The treaty with Harris had been negotiated by Ii Naosuke and it was under his auspices that the Ansei Purge was instituted. Shōin was very much of the Sonnō jōi persuasion and when many of his students and followers fell victim to the purge he called for a revolt against Ii. He received little support and all his group achieved was the assassination of Ii's manservant. He was again arrested and, in November 1859, executed at the age of just 29. His grave is in the Shōin Jinja in Tōkyō's Setagaya-ku. 

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