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.