Knowledge spillovers, driven by development and research projects, are crucial in generating new companies and services. They enhance innovation, improve competitiveness, and sustain the economic growth of nations. Hence, this paper aims to examine the relationship between knowledge spillovers and economic growth. It offers a comprehensive review of the scientific literature on the relationship between knowledge spillovers and economic growth, investigating the impact of economic cycles on knowledge spillover. Doing this provides valuable insights into how to leverage them at the different stages of the economic cycle. Hence, a PRIMA systematic review was conducted. Articles from the last 15 years were analyzed from repositories and scientific databases with a Cohen’s kappa coefficient of 0.8902. This review identifies and presents a systematic analysis of the impacts of favoring and hindering knowledge spillovers in the economic growth of a nation. These effects offer greater resilience to a nation after periods of recession. In addition, the case study of three countries is presented to illustrate the findings from the review. The results show that better utilizing knowledge spillovers to enhance economic growth depends on a functional compromise between the university, industry, and governments to understand and commit to knowledge-based economic development. Our study has implications for policymakers who aim to boost economic growth by promoting knowledge spillovers.