Introduction: To date, no studies have reported explanatory models of health-related quality of life (HRQoL) in patients with ulcerative colitis. Therefore, this study aimed to examine HRQoL and its related factors in outpatients with ulcerative colitis to construct an explanatory model. Methods: We conducted a cross-sectional survey at a clinic in Japan. The HRQoL was evaluated using the 32-item Inflammatory Bowel Disease Questionnaire. We extracted explanatory variables of HRQoL from demographic, physical, psychological, and social factors reported in previous studies and created a predictive explanatory model. The relationship between explanatory variables and the questionnaire total score was examined using Spearman’s rank correlation coefficient, the Mann–Whitney test, or the Kruskal–Wallis test. We conducted multiple regression and path analyses to examine the effect of explanatory variables on the total score. Results: We included 203 patients. Variables that were associated with the total score were the partial Mayo Score (r = −0.451), treatment side effects (p = 0.004), the Hospital Anxiety Scale-Anxiety score (r = −0.678), the Hospital Anxiety Scale-Depression score (r = −0.528), and the availability of an advisor during difficult times (p = 0.001). The model included the partial Mayo Score, treatment side effects, the Hospital Anxiety Scale-Anxiety score, and the availability of an advisor during difficult times as explanatory variables of the total score that showed the best goodness-of-fit (adjusted R2 = 0.597). The anxiety score exerted the greatest negative effect on the questionnaire total score (β = −0.586), followed by the partial Mayo Score (β = –0.373), treatment side effects (β = 0.121), and availability of an advisor during difficult times (β = −0.101). Conclusion: Psychological symptoms exerted the strongest direct effect on HRQoL in outpatients with ulcerative colitis and mediated the relationship between social support and HRQoL. Nurses should listen carefully to the concerns and anxieties of patients to ensure that a social support system is provided by leveraging multidisciplinary collaborations.