From the age of 23, he went to Edo and for 10 years studied Chinese sciences ().
He then started to study Western sciences (Rangaku) at the age of 33, with the help of the Rangaku scholar Kurokawa Ryoan (). He obtained in 1844 the "Huishoudelyk Woordboek", a Dutch translation of the encyclopedia written by the French Nöel Chomel. From the encyclopedia, he learnt how to make glass, and then magnets, thermometers, cameras and telescopes. The encyclopedia was later translated in Japanese by Utagawa Genshin under the title .
In 1849, he learned about electricity, through the book of the Dutch scientist Van den Bergh, and created Japan's first telegraph, 5 years before the gift of such a telegraph by Commodore Perry in 1854. He also invented electric machines derived from the Elekiter.
From 1842, following an analysis of the defeat of China against Great Britain in the Opium War and the spread of Western influence in Asia, Sakuma Shozan actively proposed the introduction of Western military methods to the Bakufu and the establishment of maritime defense, through his book "Eight policies for the defense of the sea" (). His writing brought some fame, and he became the teacher of several future leaders of modernization (Yoshida Shoin, Katsu Kaishu, Sakamoto Ryoma).
When Yoshida Shoin became convicted 1853 for trying to get secretely onboard one of Perry's ships to study foreign ways, Sakuma was also sentenced by association to house arrest which he endured for 9 years. During the arrest, he continued to study Western sciences, and developed various electric machines based on the elekiter and the Daniell battery, Japan's first seismic sensor, as well as improvements to guns.
After his liberation, Sakuma Shozan continued to advocate opening Japanese ports to foreign traders, as well as reinforcing the Bakufu through collaboration with the Imperial administration ().
Sakuma Shozan coined the still used phrase, "Japanese ethics, Western science" as an illustration to the way Japan ought to handle modernization.