INTRODUCTION: The comparative efficacy of advanced therapies to improve health-related quality of life (HR-QoL) in Crohn's disease (CD) is unknown. We aimed to compare the impact of approved advanced therapies for moderate-to-severe CD on HR-QoL. METHODS: We searched MEDLINE, Embase, and Cochrane CENTRAL from inception to December 2023. We included randomized controlled trials that assessed approved advanced therapies for the treatment of adults with moderate-to-severe luminal CD. The primary outcome was change from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ). Pairwise random-effects meta-analyses were conducted, and we reported results as mean differences (MDs) for continuous outcomes and risk ratios for binary outcomes, with corresponding 95% confidence intervals (CIs). A random-effects frequentist network meta-analysis was conducted, and the competing interventions were ranked using the P-score. RESULTS: Our search strategy included 34 records that fulfilled our eligibility criteria. In pairwise meta-analysis, advanced therapies were associated with improvements in IBDQ score (MD 16.07, 95% CI 12.59-19.54) after induction. In network meta-analysis, upadacitinib 45 mg ranked first for change in IBDQ after induction (MD 23.10, 95% CI 14.41-31.78, P-score 0.86). For maintenance studies, advanced therapies showed a significant improvement in IBDQ score in pairwise meta-analysis (MD 12.72, 95% CI 10.47-14.97). Infliximab 10 mg/kg ranked first for change in IBDQ after maintenance (MD 24.91, 95% CI 12.99-36.83, P-score 0.90). DISCUSSION: Advanced therapies were associated with improvements in HR-QoL after induction and maintenance. Upadacitinib 45 mg and infliximab 10 mg/kg ranked highest after induction and maintenance, respectively.