The current study aimed to examine whether asthma moderates the association between the Big Five personality traits and life satisfaction. By analyzing data from 3934 people with asthma (40.09% males) with a mean age of 49.2 (S.D. = 16.94) years old and 22,914 people without asthma (42.9% males) with a mean age of 45.62 (S.D. = 17.25) years old using a hierarchical regression and multiple regressions, the current study found that asthma significantly moderates the link between Neuroticism and life satisfaction and Openness and life satisfaction after controlling for other covariates. Specifically, Neuroticism was negatively related to life satisfaction whereas Agreeableness, Openness, Conscientiousness, and Extraversion were positively associated with life satisfaction in people with and without asthma. However, the negative association between Neuroticism and life satisfaction and the positive association between Openness and life satisfaction were stronger in people with asthma compared to people without asthma.