Neuroticism has been linked to an increased likelihood of cognitive failures, including episodes of inattentiveness, forgetfulness, or accidents causing difficulties in successfully executing everyday tasks and impacting health and quality of life. Cognitive failures associated with trait neuroticism can prompt some negative psychological outcomes and risky behaviors. Accumulating evidence shows that augmenting mindfulness can benefit cognitive health and general well-being. However, little is known regarding potential cognitive-behavioral pathways through which individual differences in trait neuroticism could influence the propensity to cognitive failures. Using a sample of 1003 undergraduate college students (females: n = 779) consisting of self-reported questionnaire data, we conducted correlational and mediational analyses to investigate the interrelationship between neuroticism, mindfulness, and cognitive failures. Higher neuroticism scores (females: r = -0.388, males: r = -0.390) and higher cognitive failures scores (females: r = -0.339, males: r = -0.407, p < .001) were significantly correlated with lower self-reported mindfulness scores. Mindfulness significantly mediated the relationship between neuroticism and cognitive failures (beta = 0.50, 95%, CI: 0.37, 0.65). These findings indicate that higher mindfulness may help ameliorate negative effects of neuroticism on everyday cognitive failures. Future research will determine how college students may benefit from positive impact of mindfulness to improve their psychological and physical health.