Background: Chemoprevention with NSAIDs, including aspirin, and anti-platelet therapy (APT), has been suggested to reduce the incidence and recurrence of hepatocellular carcinoma (HCC). This meta-analysis aimed to determine whether NSAIDs and APT use affected HCC incidence, HCC recurrence and liver-related mortality in at-risk populations with chronic liver disease. Method: Electronic databases including Pubmed, Scopus, Medline, Embase and Cochrane Library were searched (from inception to 1 October 2020) for eligible studies evaluating the impacts of NSAID or APT use on HCC incidence, recurrence and mortality. Data on HCC incidence, recurrence, liver-related mortality or bleeding complications had to be available. Studies were included if they evaluated adults with newly diagnosed HBV, HCV, ALD or NASH that were administered at least one NSAID or APT for a defined period of time and were followed for at least six-months. The primary outcome was HCC incidence. Secondary outcomes included: HCC recurrence, liver-related mortality and bleeding complications. Data were pooled using a random effects model with hazards ratios (HR) or odds ratio (OR), and 95% confidence intervals (CI) presented. Results: Of 3614 articles screened, 16 studies were included, with a total of 111,096 participants. Aspirin use significantly reduced the risk of HCC incidence (HR: 0.47, 95% CI: 0.32-0.71); and improved liver-related mortality (OR: 0.38, 95% CI: 0.29-0.49), with a small increased risk of gastrointestinal bleeding events (OR: 1.141, 95% CI: 1.06-1.23). With respect to HCC recurrence following treatment, analysis of all NSAID treatment (including aspirin-only, non-aspirin NSAIDs-only and combination NSAIDs groups) were associated with a decreased risk of HCC recurrence (HR: 0.80, 95% CI: 0.75-0.86). By stratified analysis, only the non-aspirin NSAID group showed statistical significance in risk reduction (HR: 0.73, 95% CI: 0.63-0.84). Conclusion: This study supports the use of aspirin in at-risk individuals to reduce the incidence of HCC and liver-related mortality. Funding Statement: NSW Cancer Council Linkage grant RG163222. Declaration of Interests: None of the authors declare any conflict of interest.