Reading is a crucial skill for students to develop, not only as they enter school but also as they continue throughout K-12 education. Computer-assisted instruction (CAI) is one means of providing supplemental support for students to build the foundational key areas of reading--so they can use reading to learn in later schooling years. One such CAI program that exists in the marketplace is Headsprout, which includes both an "Early Reading" and "Reading Comprehension" component. To date, no peer-reviewed studies have conducted a systematic review of the effectiveness of Headsprout on the five key areas of reading in the school setting. The most recent governmental review was completed almost a decade ago. As such, the purpose of this systematic review was to evaluate the existing literature base to determine the level of evidence for each component's effectiveness on each of the key areas of reading and identify existing avenues of future research. Results indicated tentative support for both components in some of the key areas of reading based on effect sizes, though there were a limited number of studies and the methodological rigor of included studies did not always meet What Works Clearinghouse standards. Implications for educators and researchers are discussed.