BackgroundThis systematic review aims to describe the relation between physical inactivity and healthcare costs, by taking into account healthcare costs of physical-inactivity-related diseases (common practice), including physical-activity-related injuries (new) and costs in life-years gained due to avoiding diseases (new), whenever available. Moreover, the association between physical inactivity and healthcare costs may both be negatively and positively impacted by increased physical activity.MethodsA systematic review was conducted, including records reporting on physical (in)activity in relation to healthcare costs for a general population. Studies were required to report sufficient information to calculate the percentage of total healthcare costs potentially attributable to physical inactivity.ResultsOf the 264 records identified, 25 were included in this review. Included studies showed substantial variation in the assessment methods of physical activity and in type of costs included. Overall, studies showed that physical inactivity is related to higher healthcare costs. Only one study included costs of healthcare resources used in prolonged life when physical-inactivity-related diseases were averted, showing net higher healthcare costs. No study included healthcare costs for physical-activity-related injuries.ConclusionsPhysical inactivity is associated with higher healthcare costs in the general population in the short-term. However, in the long-term aversion of diseases related with physical inactivity may increase longevity and, as a consequence, healthcare costs in life-years gained. Future studies should use a broad definition of costs, including costs in life-years gained and costs related to physical-activity-related injuries.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12913-023-09556-8.