Introduction In patients with severe chronic pulmonary diseases, there is often a need for oxygen therapy to continue after discharge from hospitalization. Long-term oxygen therapy (LTOT) has been shown to significantly reduce mortality in such patients and improve longevity by helping to correct oxygen deficiency in the bloodstream and prevent organ failure and the development of cor pulmonale (right-sided heart failure). Therefore, considering the sociocultural background of India, the objective of the present study was to evaluate patients' perceptions of LTOT using semi-structured interviews, to evaluate patients' perceptions of activities and participation, and to evaluate the quality of life (QOL) of patients with LTOT. Methodology A mixed-method study was performed at a tertiary care hospital for six months. Twenty-four chronic respiratory patients were included in the present study. The patients' perception was evaluated about LTOT using semi-structured interviews, activities, and participation using a validated activity and participation checklist and the QOL of patients with LTOT using the World Health Organization Quality of Life Brief Version (WHOQOL-BREF) questionnaire. Results Twenty-four patients were interviewed and transcripts were analyzed through thematic analysis. Descriptive statistical analysis was performed for activity and participation along with QOL.The mean age of the patients involved was 58.5 ± 9.54 years, which involved a maximum of male patients consisting of 13 (54.2%) in comparison to female patients. The duration of oxygen use in months was 31.4 ± 29.4, the daily oxygen usage in hours was 17.3 ± 6.6, and the oxygen flow rate (L/min) was found to be 2.3 ± 0.97 at rest and 3.6 ± 1.4 on activity. In addition, the oxygen use by the patients was preferable as prescribed by 15 (62.5%) patients. Patients' perspectives on LTOT demonstrated that 10 (41.7%) patients perceived oxygen as relieving symptoms while most patients used oxygen during walking indoors activity involving 22 patients (91.7%), with 17 (77.3%) reporting improved ability and five (22.7%) facing obstacles. Instrumental activities involving walking shorter distances (less than 1 km) involved a high usage of oxygen with 20 patients (83.3%) using it, where 15 (75%) found it beneficial, three (15%) encountered obstacles, and two (10%) noted no effect from its use. Social interaction found that only one patient (4.20%) used oxygen at work, finding it helpful, but the majority, 20 (83.4%), did not go to work at all. Moreover, oxygen usage during transportation reported that travel using private vehicles involved a maximum of patients (16, 66.7%). Furthermore, for inquiries related to QOL, the results demonstrated that for the four domains of WHOQOL-BREF, consisting of physical health, psychological, social relationships, and environment, the mean values were found to be 48.33 ±10.66, 54.79 ± 13.7, 55.75 ±11.1, and 60.25 ± 12.6, respectively. Conclusion LTOT has been perceived to be a life-saving intervention by majority of the chronic respiratory disease patients of increased severity. Patients experienced various issues in daily activities and participation, which have affected their QOL. Overall, a lack of awareness and knowledge regarding the purpose, dosage, benefit, and usage of oxygen therapy was found to be evident and needs to be focused.