Background: Out-of-pocket health expenditures (OOPHE) in primary care can pose a significant financial burden on individuals and households, particularly in low- and middle-income countries. Understanding the factors influencing OOPHE is crucial for developing effective policies to improve healthcare access and affordability. Objective: This systematic review aimed to identify and analyze the factors influencing OOPHE in primary care settings across high-, middle-, and low-income countries. Methods: A comprehensive search of electronic databases was conducted to identify relevant studies. Included studies were assessed for quality and data were extracted to identify key factors influencing OOPHE. Results: Demographic characteristics, socioeconomic factors, healthcare utilization, system factors, and cultural factors were all found to influence OOPHE. Lower income levels, limited insurance coverage, frequent healthcare utilization, and higher disease severity were consistently associated with higher OOP costs. Conclusion: The findings highlight the significant burden of OOP expenditures on individuals and households. Policymakers should prioritize strategies to expand health insurance coverage, improve access to primary care services, negotiate lower prices for healthcare goods, and address underlying socioeconomic factors. Further research is needed to explore the impact of specific interventions and the role of cultural factors in shaping OOP expenditures.