An umbrella review of the relationship between nonsteroidal anti-inflammatory drugs (NSAIDs) and cancer incidence found that NSAIDs, particularly aspirin, may reduce the risk of several cancers, including breast, central nervous system (CNS), esophageal, gastric, head and neck, hepatocellular, cholangiocarcinoma, colorectal, endometrial, lung, ovarian, prostate, and pancreatic cancers. However, regular intake of non-aspirin NSAIDs (NA-NSAIDs) may increase the risk of kidney cancer. Most included studies were of low quality, and potential side effects, such as hemorrhage, digestive symptoms, and peptic ulcers, limit their regular use for cancer prevention. Aspirin use was associated with a reduced risk of several cancers, including breast, cholangiocarcinoma, colorectal, endometrial, esophageal, gastric, liver, lung, ovarian, prostate, and pancreatic cancers, but no significant association was found with bladder, CNS, head and neck, melanoma, kidney, or skin cancers. NA-NSAIDs were associated with a reduced risk of CNS, colorectal, esophageal, gastric, and skin cancers but increased risk of kidney cancer. Dose-response analyses showed that higher NSAID intake was linked to lower cancer risks in some cancers. However, heterogeneity and publication bias were observed in many studies. The quality of evidence for most cancer outcomes was low or very low. Despite potential benefits, the side effects of NSAIDs and the low quality of evidence suggest that regular use for cancer prevention is not recommended. Further high-quality studies are needed to better understand the relationship between NSAID use and cancer outcomes.An umbrella review of the relationship between nonsteroidal anti-inflammatory drugs (NSAIDs) and cancer incidence found that NSAIDs, particularly aspirin, may reduce the risk of several cancers, including breast, central nervous system (CNS), esophageal, gastric, head and neck, hepatocellular, cholangiocarcinoma, colorectal, endometrial, lung, ovarian, prostate, and pancreatic cancers. However, regular intake of non-aspirin NSAIDs (NA-NSAIDs) may increase the risk of kidney cancer. Most included studies were of low quality, and potential side effects, such as hemorrhage, digestive symptoms, and peptic ulcers, limit their regular use for cancer prevention. Aspirin use was associated with a reduced risk of several cancers, including breast, cholangiocarcinoma, colorectal, endometrial, esophageal, gastric, liver, lung, ovarian, prostate, and pancreatic cancers, but no significant association was found with bladder, CNS, head and neck, melanoma, kidney, or skin cancers. NA-NSAIDs were associated with a reduced risk of CNS, colorectal, esophageal, gastric, and skin cancers but increased risk of kidney cancer. Dose-response analyses showed that higher NSAID intake was linked to lower cancer risks in some cancers. However, heterogeneity and publication bias were observed in many studies. The quality of evidence for most cancer outcomes was low or very low. Despite potential benefits, the side effects of NSAIDs and the low quality of evidence suggest that regular use for cancer prevention is not recommended. Further high-quality studies are needed to better understand the relationship between NSAID use and cancer outcomes.