Background: In the United States, cancer is the second leading cause of mortality, and millions more battle cancer worldwide. As such, primary prevention of cancer is a major interest globally. Aspirin has been studied as a primary prevention method for multiple diseases, mainly cardiovascular disease and various forms of cancer. The role of aspirin as a primary prevention of cancer is still controversial and may be more beneficial in certain cancers over others. With rapidly surfacing large randomized controlled trials (RCTs) studying this subject, we aimed to evaluate the efficacy and safety of aspirin as a primary prophylaxis for cancer. Methods: A comprehensive electronic database search was conducted for all RCTs that compared aspirin versus placebo for the prevention of any type of disease, and where cancer incidence or mortality was reported. The primary outcome was cancer-related mortality. Secondary outcomes were cancer incidence, all-cause mortality, major bleeding, any bleeding and gastrointestinal (GI) bleeding. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) using a random-effects model at the longest follow-up period. Results: We included 16 RCTs with 104,018total patients, mean age of 60.51 years, mean follow-up of 5.48 years, and a male percentage of 38.72%. We found that aspirin was not associated with a significant reduction of cancer-related mortality compared with placebo (RR 0.99; 95% CI: 0.87-1.12; P = 0.85: I²= 41%). Compared with placebo, aspirin was not associated with significant reduction of all-cause mortality (RR 0.97; 95% CI: 0.92-1.02; P = 0.19; I²= 13%) or cancer incidence (RR: 0.98; 95% CI: 0.92-1.04; P = 0.43; I²= 16%). However, aspirin treatment was associated with significantly increased risks of any bleeding (RR 1.63; 95% CI: 1.31-2.03; P < 0.01), major bleeding (RR 1.41; 95% CI: 1.26-1.57; P < 0.01), and GI bleeding (RR 1.85; 95% CI: 1.38-2.48; P < 0.01) compared with placebo. Conclusions: Our study did not find any significant reductions in cancer-related mortality or cancer incidence when compared with placebo. Our study also highlights the dangers of aspirin for primary prevention of cancer as aspirin was found to cause higher rates of bleeding (any bleeding, major bleeding, and GI bleeding) compared to placebo at the longest follow-up period with no significant benefit in cancer primary prevention.