Formerly known as Kaohsiung Polytechnic Institute, ISU was established in 1986 by I-Shou Lin, the founder of E United Group (義联集團), to commemorate his mother as well as to benefit the villages and towns where he started his business.

KPI was officially renamed I-Shou University on August 1, 1997.

The Medical Campus, across from E-DA Hospital in Yanchao District of Kaohsiung City, was opened in 2006 to accommodate the College of Medicine.

In 2010 ISU was approved by the Ministry of Education to establish the School of Chinese Medicine for Post Baccalaureate and three years later the School of Medicine for International Students with all courses taught in English in 2013.

In 2018, ISU gained approval from the Ministry of Education to establish a six-year, government-funded MD program for Taiwanese citizens, and welcomed its inaugural class in 2019.