In 1638, the Tokugawa shogunate established two medicinal herb gardens in the Azabu and Otsuka neighborhoods of Edo, the city that would become Tokyo. When the Azabu garden was abolished in 1684, the fifth shogun, Tokugawa Tsunayoshi, relocated it to Koishikawa, onto the grounds of his own villa. The herb garden thrived under subsequent rulers. The eighth shogun, Tokugawa Yoshimune, expanded it to cover nearly 15 hectares and turned it into a powerhouse of practical botany during the Kyoho period. Tons of herbal medicines were produced each year for the shogunate and the public. In 1735, a scholar named Aoki Konyo conducted experimental cultivation of sweet potatoes within the garden walls, a project that would eventually help save lives during Japan's frequent famines by establishing the crop across the country.

Yoshimune was known as the reformist shogun, and his famous suggestion box, placed at the entrance to Edo Castle, invited petitions from ordinary citizens. In 1722, a town doctor named Ogawa Tadafune submitted a plea for a medical clinic to treat the poor. Yoshimune ordered the Edo magistrate, the legendary Ooka Tadasuke, to establish the Koishikawa Yojosho within the garden grounds. The clinic became one of Edo's most important charitable institutions, providing medical care to commoners who could not afford private physicians. It was a radical act of public health in an era when feudal hierarchy rigidly separated social classes. The clinic operated for over a century, and its site within the botanical garden is still commemorated today.

After the Meiji Restoration in 1877, the garden was transferred to the newly founded Tokyo Imperial University, now the University of Tokyo. It became the birthplace of modern botanical research in Japan. Scientists cataloged, classified, and studied the rich collections that the shogunate had spent two centuries assembling. Today the garden's research focuses on the evolution, phylogenetic systematics, and physiology of higher plants. Its herbarium holds 1.4 million specimens, and its library contains 20,000 books and journals. The living collections include 1,400 hardy woody species, 1,500 hardy herbaceous species, and 1,100 tropical and subtropical species, with particular strength in wild-collected specimens from Japan, Korea, Taiwan, and China.

The garden's most beloved curiosities are its memorial trees. Newton's apple tree arrived through a chain of scientific generosity: in 1964, Dr. Sutherland, Director of England's Institute of Physics, gave a grafted branch to Dr. Yuji Shibata of the Japan Academy. The cutting was infected with a virus and had to be quarantined and treated at the garden before finally being planted in 1981. Mendel's grapevine carries an even more poignant story. Japanese scientists in the 1980s discovered that the original vine had disappeared from the monastery in Brno where Mendel conducted his genetics experiments. A cutting from the Koishikawa vine was sent back to the Czech Republic to restore the species at its birthplace. In 2012, the Japanese government designated the entire garden as both a National Place of Scenic Beauty and a National Historic Site, ensuring that this layered landscape of science, medicine, and power endures.