After graduating from Franklin and Marshall College (1882) and Lancaster Theological Seminary (1885), Hoy was ordained and appointed by the Reformed (German) Church in the United States and sailed for Japan in 1885. He quickly identified Sendai in northern Japan as strategic, and upon arrival there in January 1886 launched a small school for training Japanese pastors, while also carrying on active evangelistic work. He helped start a girls' school, now Miyagi Gakuin, and the following year married Mary Ault, one of its teachers. In 1891 Hoy's school became Tohoku Gakuin (North Japan University).
Burdened with a wide variety of responsibilities, including publication of a bimonthly English journal, the Japan Evangelist, and suffering from asthma, he went to Shanghai in 1898 for a three-month health furlough. After traveling up the Yangtze to Hankow, he determined to launch a mission in Hunan Province, resigned from the Japan Mission, and in 1900 settled at Yochow. For 25 years Hoy was at the center of a rapidly developing program of schools for boys and girls, evangelistic outstations, and medical work. He was granted the D.D. by Franklin and Marshall (1903) and the LL.D. by Heidelberg College (1925). In the turmoil of revolutionary civil war, the Hoys were evacuated in 1927, and William Hoy died on shipboard. His daughters Gertrude and Mabel also served as missionaries in China.