The purpose of this systematic review is to synthesize existing empirical research on physically chronically ill college student well-being, focusing specifically on individual- and institution-level factors that could become targets for future intervention and research. This review was conducted to answer the following research question: What malleable student-level and institution-level factors are related to well-being for students with physical chronic illnesses in four-year higher education programs? The electronic databases Academic Search Complete, EBSCO EJS, and ProQuest Central were searched for peer reviewed empirical studies published between 1990 and 2021. A process of citation chaining and a scan of sources from other relevant literature reviews were used to locate additional articles. The results of this review offer three major implications. First, with only 13 studies identified in the literature, there is a critical need for additional research investigating well-being for physically chronically ill college students. Second, the correlational nature of the extant literature does not elucidate the causal directionality of the relationships among the variables of interest. For example, although findings have correlated physical chronic illness and poor mental health outcomes, it remains unknown how causality operates, which can create challenges as institutional leaders determine how to effectively support this group. Third, no studies to date have investigated institutional practices that may result in increased well-being for these students. Future researchers and institutional leaders should support a decrease in negative outcomes along with mechanisms to increase experiences of well-being to advance opportunities for physically chronically ill students to flourish.