Exposure to natural greenspace benefits health through direct and indirect pathways: increasing physical activity, improving mental health, relieving social isolation, reducing exposure to extreme temperature, noise, and air pollution. Understanding the etiologic pathway of greenspace and health is needed. Here, we used a large cohort follow-up data from the U.K. Biobank to quantify the magnitude of behavioural factors, psychological factors, biomarkers/physiological measurements, co-morbid diseases, and environmental exposure as potential mediators in the relationship between greenspace and mortality. We estimated hazard ratios (HR) with Cox proportional hazards models, and undertook exploratory mediation analyses to quantify the relative contribution of five types of mediators. Our results indicate greenspace was strongly associated with lower mortality risks [per IQR of public greenspace (HR = 0.90 (95% CI 0.86-0.84)) and domestic gardens (HR = 0.91, (95% CI 0.88-0.94))]. The protective associations were especially pronounced among those with lower individual-level socioeconomic status or living in places with area-level deprivation. Exploratory mediation analysis detected benefits in pathways through reducing air pollution, relieving social isolation and depression, increased physical activity and time spent outdoor, better lung function (FEV1/FVC), and having higher serum vitamin D levels.