As it becomes more crucial to push the boundaries of science to develop new technologies and important global initiatives, internationalization can be instrumental in helping underdeveloped countries overcome challenges such as poverty, climate change, and educational inequalities. Higher education institutions have always faced challenges in the process of internationalization, which have occupied scholarly attention in recent decades, but little research has been conducted on the internationalization of higher education in less developed African countries. This qualitative study aims to shed light on the challenges of internationalization of higher education in low-income countries in East Africa. After reviewing the literature and interviewing academics, the obtained data were thematically analyzed. The results suggested 12 main challenges, which were classified into four major categories. The challenges include a lack of clear policies and guidelines; the inefficiency of the organizational structure of internationalization; financial, infrastructure, and equipment problems; weaknesses in scientific, skill, and language competences; cultural differences; non-reciprocal relationships; and a brain drain. Finally, strategies for responding to these challenges with regard to the internal and external environments of higher education institutions were proposed. Among the internal strategies of higher education institutions are the development of clear policies and visions, planning for the development of human resources, and sustainable budgeting for internationalization programs. External strategies emphasize the development of national policies and laws based on contextual and environmental conditions, as well as interaction and participation in international meetings to expand communication and use the scientific and economic capacities of international agencies and institutions.