Background: Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic and disabling diseases that affect patient health-related quality of life (HRQoL). IBD patients are frequently exposed to high levels of stress and psychological distress. Biological drugs have been proven to reduce inflammation, hospitalization, and most of the complications that characterize IBDs; their potential contribution to patients’ HRQoL remains to be explored. Aim: To evaluate and compare any change in the HRQoL and markers of inflammation in IBD patients undergoing biological drugs (infliximab or vedolizumab). Material and Methods: A prospective observational study was conducted on a cohort of IBD patients, aged >18 years, who were prescribed with infliximab or vedolizumab. Demographic and disease-related data at baseline were collected. Standard hematological and clinical biochemistry parameters, including C-reactive protein (CRP), white blood cells count (WBC), erythrocytes sedimentation rate (ESR), and α1 and α2 globulins were measured after a 12-h fast at baseline (T0), after 6 weeks (T1), and at 14 weeks (T2) of biological treatment. Steroid use, disease activity as measured by the Harvey–Bradshaw index (HBI) and partial Mayo score (pMS) for the CD and UC, respectively, were also recorded at each timepoint. The Short Form 36 Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy (FACIT-F), and Work Productivity and Activity Impairment–General Health Questionnaire (WPAI:GH) were administered to each patient at baseline, T1, and T2 to address the study aims. Results: Fifty eligible consecutive patients (52% with CD and 48% with UC) were included in the study. Twenty-two patients received infliximab and twenty-eight received vedolizumab. We noted a significant reduction in the CRP, WBC, α1, and α2 globulins from T0 to T2 (p= 0.046,p= 0.002,p= 0.008, andp= 0.002, respectively). Participants showed a significant decrease in steroid administration during the observation period. A significant reduction in the HBI of CD patients at all three timepoints and a similarly significant decrease in the pMS of UC patients from baseline to T1 were recorded. Statistically significant changes were observed in all questionnaires during follow-up as well as an overall improvement in the HRQoL. The interdependence analysis carried out between the biomarkers and the scores of the individual subscales showed a significant correlation between the variation (Δ) of the CRP, Hb, MCH, and MCV with physical and emotional dimensions of the SF-36 and FACIT-F tools; work productivity loss expressed by some of the WPAI:GH items negatively correlated with the ΔWBC and positively with the ΔMCV, ΔMCH, and Δ α1 globulins. A sub-analysis according to the type of treatment showed that patients receiving infliximab experienced a more pronounced improvement in their HRQoL (according to both SF-36 and FACIT-F) compared with patients receiving vedolizumab. Conclusions: Both infliximab and vedolizumab played an important role in contributing to the improvement of the HRQoL in IBD patients by also reducing inflammation and, consequently, steroid use in patients with an active disease. HRQoL, being one of the treatment goals, should also be assessed when taking charge of IBD patients to assess their clinical response and remission. The specific correlation between the biomarkers of inflammation and life’s spheres, as well as their possible role as clinical markers of HRQoL, should be further investigated.