Born in 1843 as the eldest son of Niijima Tamiji, a retainer of Annaka Domain in Kozuke, at the domain's residence in Edo. His childhood name was Shimeta. He studied Confucianism at the domain school, and later took up Dutch and English studies. Through an encounter with a Chinese translation of the Bible, he came to seek the 'true Lord' of scripture, and in 1864 broke the law by stowing away on the American brig Berlin from Hakodate. He reached Boston the following year, where the ship's owner Alpheus Hardy and his wife took him in, and he was baptized under the name Joseph Hardy Neesima. After studying at Phillips Academy, Amherst College, and Andover Theological Seminary, he returned to Japan in 1874. With the support of the American Board, in 1875 he opened Doshisha English School in Kyoto (at founding, eight students and two teachers). Together with Yamamoto Kakuma and his wife Niijima Yae, he built a Christian institution of higher education. He ruined his health striving to raise it to a theological school and a full university, and in 1890 closed his 48-year life at Oiso in Kanagawa. His dying wish was reported to be 'May there arise strong men filled in every fiber with conscience.'

A quiet man of passion. He did not overawe, calling students 'gentlemen' and treating them as equals. He rendered the English 'conscience' as 'free conscience' in Japanese and made it the core of Doshisha's education. Despite poor health, he wore himself out in travel and in the work of opening schools, burning through his short life of 48 years.

Doshisha developed into a theological school and then a full university, producing figures such as Tokutomi Soho, Ukita Kazutami, and Yamaji Aizan, and became a center of Meiji Christian culture. Its founding spirit of 'freedom, Christianity, and internationalism' has continued to exert great influence on Japanese private-school education before and after the war. In 1889 Amherst College honored his achievement with the first honorary doctorate ever granted to a Japanese.