Background: Inflammation is a common pathogenic pathway underlying multiple chronic conditions and contributes to the decline in healthspan. This study aimed to evaluate the effect of low-dose aspirin on the loss of healthspan in older adults. Methods: The ASPirin in Reducing Events in the Elderly (ASPREE) trial was a double-blind, placebo-controlled, randomised study assessing the effect of daily low-dose aspirin for primary prevention. Community-dwelling participants aged ≥70 years (or ≥65 years for United States minority ethnic groups) were recruited from Australia and the United States. Eligible participants were free of major diseases at baseline and had a life expectancy of more than five years. Participants were randomly assigned to receive 100 mg of aspirin daily or placebo. Loss of healthspan was defined as the first occurrence of cardiovascular disease, diabetes, dementia, cancer, or death. Results: A total of 19,114 participants were followed for a median of 4.7 years, during which 5,835 participants (30.5%) experienced loss of healthspan. Older age, male sex, smoking, hypertension, and frailty were associated with a higher likelihood of healthspan loss. The incidence rates were 82.1 and 82.7 events per 1,000 person-years in the aspirin and placebo groups, respectively. There was no evidence of a significant difference in the risk of healthspan loss between the two groups (hazard ratio 0.98; 95% CI: 0.92–1.05). Conclusion: Low-dose aspirin did not reduce the rate of healthspan loss among older community-dwelling adults. Future research should focus on lifestyle and behavioural interventions to promote healthy ageing and extend healthspan.