Adopting a healthy lifestyle, including regular physical activity, is widely believed to decrease cancer risk. This study aimed to quantitatively establish the dose-response relationships between total physical activity and the risk of breast, colon, lung, gastric, and liver cancers. A systematic review and dose-response analysis were conducted using PubMed and Embase from January 1, 1980 to March 20, 2023. Prospective cohort studies that examined the association between physical activity and the risks of any of the 5 outcomes were included. The search was confined to publications in the English language with a specific focus on human studies. Physical activity is standardized by using the data from US National Health and Nutrition Examination Surveys (NHANES) and the Global Burden of Disease 2019 database. A total of 98 studies, involving a combined population of 16,418,361 individuals, were included in the analysis. Among the included studies, 57 focused on breast cancer, 17 on lung cancer, 23 on colon cancer, 5 on gastric cancer, and 7 on liver cancer. Overall, elevated levels of physical activity exhibited an inverse correlation with the risk of cancer. The dose-response curve for lung cancer exhibited a non-linear pattern, with the greatest benefit risk reduction observed at 13,200 MET-minutes/week of physical activity, resulting in a 14.7% reduction in risk (relative risk 0.853, uncertainty interval 0.798 to 0.912) compared to the inactive population. In contrast, the dose-response curves for colon, gastric, breast, and liver cancers showed linear associations, indicating that heightened levels of total physical activity were consistently associated with reduced cancer risks. However, the increase in physical activity yielded a smaller risk reduction for colon and gastric cancers compared to breast and liver cancers. Compared to individuals with insufficient activity (total activity level < 600 MET-minutes/week), individuals with high levels of activity (≥ 8,000 MET-minutes/week) experienced a 10.3% (0.897, 0.860 to 0.934) risk reduction for breast cancer; 5.9% (0.941, 0.884 to 1.001) for lung cancer; 7.1% (0.929, 0.909 to 0.949) for colon cancer; 5.1% (0.949, 0.908 to 0.992) for gastric cancer; 17.1% (0.829, 0.760 to 0.903) for liver cancer. This study demonstrated a significant inverse relationship between total physical activity and the risk of breast, gastric, liver, colon, and lung cancers.