Zoonotic spillover events pose a significant and growing threat to global health. By focusing on preventing these cross-species transmissions, we can significantly mitigate pandemic risks. This review aims to analyze the mechanisms of zoonotic spillover events, identify key risk factors, and propose evidence-based prevention strategies to reduce future pandemic threats. Through a comprehensive literature review and analysis of major databases including PubMed, Web of Science, and Scopus from 1960–2024, we examined documented spillover events, their outcomes, and intervention strategies. This article emphasizes that targeting the root cause—the spillover event itself—is key to averting future pandemics. By analyzing historical and contemporary outbreaks, we extract crucial insights into the dynamics of zoonotic transmission. Factors underlying these events include increased human–animal contact due to habitat encroachment, agricultural intensification, and wildlife trade. Climate change, global travel, and inadequate healthcare infrastructure exacerbate risks. The diversity of potential viral reservoirs and rapid viral evolution present major challenges for prediction and prevention. Solutions include enhancing surveillance of wildlife populations, improving biosecurity measures, investing in diagnostic capabilities, and promoting sustainable wildlife management. A “One Health” approach integrating human, animal, and environmental health is crucial. Predictive modelling, international cooperation, and public education are key strategies. Developing pre-exposure prophylactics and post-exposure treatments is essential for mitigating outbreaks. While obstacles remain, advances in genomics and ecological modelling offer hope. A proactive, comprehensive approach addressing the root causes of spillover events is vital for safeguarding global health against future pandemics.