Abstract Objectives The association between physical activity and venous thromboembolism (VTE) remains unclear. Therefore, we investigated the prospective dose–response associations between accelerometer-measured intensity-specific physical activity and new-onset VTE, accounting for genetic risk. Methods and results In total, 85 116 participants from the UK Biobank were included. Incident VTE was identified via linked hospital records and death registries. A weighted polygenic risk score (PRS) was used to quantify genetic risk for VTE, with higher values indicating a high genetic risk. Cox proportional hazard models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) of the associations. Overall, 1182 incident VTE cases were documented during a median follow-up of 6.18 years. In the overall study population, the participants in the highest level of the total volume of physical activity [0.60 (0.45, 0.79)], moderate-to-vigorous-intensity physical activity [0.66 (0.51, 0.86)], and light-intensity physical activity [0.66 (0.51, 0.85)] had lower adjusted HRs (95% CIs) for VTE than those of participants in the lowest level. Both the total volumes of physical activity and light-intensity physical activity were negatively associated with VTE risk in participants with low, intermediate, and high PRS. However, moderate-to-vigorous-intensity physical activity was only protective against VTE in participants with low and intermediate PRS, with a significant interaction (P for interaction = 0.02). Conclusion Higher levels of physical activity of any intensity were associated with a lower risk of new-onset VTE. However, the negative association between moderate-to-vigorous-intensity physical activity and new-onset VTE was significant only in participants with low and intermediate genetic predispositions to VTE.