Background: Obstructive sleep apnea (OSA) is often associated with decreased health-related quality of life (HRQoL). The aims of this study were to evaluate HRQoL, the clinical and psychological profile of suspected or verified OSA patients, and the impact of PAP therapy at 1-year follow-up. Methods: At T0, OSA-suspected subjects underwent clinical, HRQoL, and psychological assessment. At T1, OSA patients underwent PAP therapy in a multidisciplinary rehabilitation setting. At 1 year follow-up, OSA patients were evaluated for the second time. Results: At T0, OSA patients (n = 283) and suspected OSA subjects (n = 187) differed for AHI, BMI, and ESS. At T0, the PAP-treatment group (n = 101) showed moderate–severe anxious (18.7%) and depressive (11.9%) symptoms. At 1 year follow-up (n = 59), the sleep breathing pattern had normalized and there was a reduction of ESS scores and anxious symptoms. There was also an improvement in HRQoL (0.6 ± 0.4 vs. 0.7 ± 0.5, p = 0.032; 70.4 ± 19.0 vs. 79.2 ± 20.3, p = 0.001) and in satisfaction with sleep quantity (52.3 ± 31.7 vs. 71.4 ± 26.2, p = 0.001), sleep quality (48.1 ± 29.7 vs. 70.9 ± 27.1, p = 0.001), mood (58.5 ± 24.9 vs. 71.0 ± 25.6, p = 0.001), and physical resistance (61.6 ± 28.4 vs. 67.8 ± 27.4, p = 0.039). Conclusion: Considering the impact of PAP treatment on patients’ psychological and HRQoL evaluations that we observed, our data are valuable for unveiling different profiles characterizing this clinical population.