Background <p>Oxygen refers to a colorless, odorless, tasteless gas that is essential for proper body functioning and survival. However, the effectiveness of oxygen therapy can be influenced by the perceptions of patients and caregivers. Understanding patients’ and caregivers’ perceptions of oxygen therapy directly impacts healthcare practices. Consequently, the information gained from such research can be used to develop interventions that can help promote oxygen therapy’s benefits, leading to the acceptance and compliance with oxygen as treatment. This studied aimed to explore the perception of patients and caregivers towards oxygen therapy in Mbale Regional Referral Hospital (MRRH).</p> Methods <p>This study was conducted in Mbale Regional Referral Hospital involving in-depth interviews with patients and caregivers. The study employed a descriptive qualitative study. The qualitative data collected was thematically analyzed using the Braun and Clerk’s six step approach. The sampling technique was purposive sampling, sample size determination involved saturation sampling technique and the data collection tool used was in-depth interview guides. A total of 46 interviews were conducted including 16 patient interviews and 30 caregiver interviews.</p> Results <p>Both patients and caregivers perceived oxygen therapy as a life-saving yet fear-inducing intervention, spiritual and emotional interpretations of oxygen therapy, perceived physical and technological aspects of oxygen therapy. Both patients and caregivers reported that their information about oxygen therapy was mainly obtained from schools, communities, hospitals, and the internet.</p> Conclusions <p>The perceptions of patients and caregivers towards oxygen therapy do not necessarily differ from each other. Patients and caregivers perceived oxygen therapy in terms of; oxygen therapy perceived as a symbol of impending death like oxygen equals the end-of-life; emotional and psychological distress caused by oxygen therapy like fear and anxiety; spiritual and faith-based interpretations of oxygen therapy like attribution of survival to divine interventions. We recommend the implementation of community sensitization campaigns and health education programs on oxygen therapy to improve awareness and understanding of oxygen therapy. In addition, counselling and psychological support should be provided to patients and caregivers struggling with emotional distress and fear related to oxygen therapy. Further research is needed to assess the effectiveness of health education and awareness interventions in improving the perceptions of patients and caregivers towards oxygen therapy.</p>