With the shift in clinical paradigms over the past decade toward value-based healthcare, quality of life (QoL) has become a critical measure of treatment success in chronic endocrine conditions such as autoimmune hypothyroidism (AH). Many patients report persistent symptoms despite achieving biochemical euthyroidism, underscoring the need for patient-reported outcome (PRO) assessment. This study assessed health-related quality of life (HRQoL) in newly diagnosed AH patients before and after levothyroxine therapy, compared to healthy controls. The goal was to evaluate whether normalization of thyroid hormone levels translates into meaningful improvements in patient-reported well-being. A Prospective cohort of 64 AH patients (20–65 years) was evaluated using the ThyPRO-39 questionnaire. Patients completed the instrument at diagnosis and after four months of levothyroxine therapy. Their responses were compared with those of 64 age and sex matched healthy individuals. AH patients demonstrated significantly impaired QoL at baseline compared to controls, as indicated by higher composite ThyPRO-39 scores (p = 0.015). Following levothyroxine therapy, patients exhibited statistically and clinically significant improvement across multiple domains, with a significant reduction in composite scores (p < 0.001). Notably, patients with overt hypothyroidism experienced greater improvements than those with subclinical disease. Despite significant improvements following levothyroxine therapy, some QoL deficits persisted, particularly in cognitive and psychosocial domains. These impairments may reflect the effects of thyroid autoimmunity and psycho-social factors rather than hormone deficiency alone. These findings highlight the importance of incorporating validated tools such as ThyPRO-39 into routine clinical practice in Moldova to capture patient-reported outcomes beyond biochemical parameters and to support more personalized management.