The assessment of health-related quality of life (QoL) in chronic conditions is considered as relevant, especially in patients with hypothyroidism where a high comorbidity with depressive and anxiety issues is reported. The present cross-sectional pilot study aims at: i) examining the correlation of thyroid-specific and generic measures of QoL in patients with Hashimoto’s Thyroiditis (HT); ii) investigating the associations of generic and thyroid-specific measures of QoL with depression and anxiety in patients with HT; iii) comparing generic and thyroid-specific measures of QoL in patients with HT versus controls. Twenty-one patients with serologically and/or ultrasonographically verified HT and sixteen controls with non-toxic goiter or post-surgical hypothyroidism were recruited for this study. Generic and disease-specific QoL were assessed by Health Survey Short Form-36 (SF-36) and Thyroid Patient Reported Outcome (ThyPRO) questionnaires, respectively, whereas depression and anxiety were measured through Beck Depression Inventory-second edition (BDI-II) and Hamilton Anxiety Rating Scale (HAM-A) questionnaires, respectively. Findings showed that ThyPRO and SF-36 scores were associated with each other only regarding the mental health domain, and that such QoL measures were consistently associated with depression levels but not with anxiety. Besides, no statistically significant difference was found between patients with HT and controls with regard to generic and thyroid-specific QoL. The present study suggests that generic and disease-specific measures of QoL can sufficiently assess the mental functioning domain and capture depressive symptoms, but only thyroid-specific measures (such as ThyPRO) can provide an accurate examination of physical aspects of QoL and the overall disease impact in patients’ lives. Besides, some methodological limitations should be taken into account in both using generic and disease-specific instruments with regard to their tendency to underestimate possible anxiety problems.