Background. This study is aimed at determining the quality of life, mental health, and adherence to continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea (OSA) among Thai OSA patients during the coronavirus disease 2019 (COVID-19) pandemic as this data has been lacking. Methods. A cross-sectional study was conducted at a university hospital between September 2021 and April 2022. OSA patients aged 18 years or older who required home CPAP treatment were included. Sleep Apnea Quality of Life Index (SAQLI) and Depression Anxiety Stress Scales-21 (DASS-21) were used to assess quality of life and mental health, respectively. Results. A total of 142 participants (62% male) were included, with a mean age of 54.4±14.7 years and a body mass index of 29.9±6.8 kg/m2. Polysomnographic data showed a mean apnea-hypopnea index of 48.0±32.4 events/hour and a mean lowest oxygen saturation of 79.2±12.2%. Severe OSA was observed in 66.9%. CPAP compliance was reported in 50.7%. The SAQLI score was 2.32±1.12. Depression, anxiety, and stress scores in DASS-21 were 2.89±3.31, 3.94±3.67, and 4.82±4.00, respectively. Compared to the CPAP compliance group, the CPAP noncompliance group had higher daily activity scores in SAQLI (2.98±1.25 vs. 2.45±1.33, P=0.015). Conclusions. The quality of life for Thai OSA patients during the COVID-19 era was moderate degree. Poor CPAP compliance was significantly associated with limited daily activity. Enhancing CPAP compliance could improve the quality of life in these patients. This trial is registered with TCTR20211104004.