Background and Aim: Normalizing health-related quality of life (QoL) and fatigue are important long-term treatment targets in inflammatory bowel disease (IBD). We examined their evolution in relation to changes in disease activity during vedolizumab therapy. Methods: Cohort study of biologically refractory IBD patients treated with vedolizumab. Patients were prospectively evaluated at all infusions by Short Health Scale (SHS) (QoL questionnaire covering four health dimensions) (n = 79), visual analogous scale for fatigue (VAS-F) (n = 30), and clinical disease activity. Objective disease assessment was carried out after 1 year or at treatment failure. Results: Patients in steroid-free clinical remission at end of induction improved significantly in all SHS items already from week 2 with full implementation by week 14 (“Symptoms” 59% improvement, P < 0.001; “Function” 63%, P < 0.001; “Worries” 59%, P < 0.001; “Well-being” 40%, P < 0.01). Then, SHS remained stable at background levels (< 20) for 1 year (improvements 67%; 65%; 62%; 57%; P < 0.001). Combined clinical-objective remission at 1 year was associated with highest SHS improvements (64–72%; P < 0.001). Of note, early SHS improvements preceded manifestation of clinical remission in most patients (22 of 33; 67%). Clinical response materialized into late (week 6 or later) and minor SHS improvements (31–46%, P < 0.001). Fatigue improved steadily over 6 months to background levels (VAS-F < 4) among patients in clinical remission (45% decrease) or clinical-objective remission (41%). SHS and VAS-F impairment remained elevated in patients without effect of therapy. Conclusion: QoL rapidly improves and predicts later significant clinical-objective efficacies of vedolizumab at end of induction and 1 year. Fatigue improves slowly after remission is attained.