Physical inactivity is a major risk factor for numerous non-communicable diseases which dominate the overall burden of disease in Switzerland. We aimed to estimate the burden attributable to adult physical inactivity in Switzerland and its three culturally different language regions from a societal perspective in terms of disability-adjusted life years (DALYs), medical costs, and productivity losses. The burden of physical inactivity was estimated with a population attributable fractions (PAFs) approach. PAFs were calculated based on the prevalence of physical inactivity in the Swiss Health Survey and literature-based adjusted risk ratios of disease incidence. These PAFs were then applied to the total burden of the diseases related to physical inactivity. Physical inactivity was responsible for 2.0% (95%CI 1.7%-2.2%) of total DALYs lost and 1.2% (95%CI 1.0%-1.3%) of total medical costs in 2013. This is equivalent to 116 (95%CI 99-135) Swiss francs per capita per year. Productivity losses were valued at 117 (95%CI 94-142) Swiss francs per capita per year. The two diseases which caused the highest economic burden were low back pain and depression. The analysis of regional differences revealed that the per capita burden of physical inactivity is about twice as high in the French- and Italian-speaking regions compared to the German-speaking region. Reasons include a higher prevalence of physical inactivity, higher per capita health care spending, and higher disease prevalence. Cost-effectiveness analysis of related interventions should consider regional differences for optimal resource allocation in physical activity promotion policies.