Qualitative insights regarding psycho-social barriers and challenges experienced by drug-resistant tuberculosis (DR-TB) patients and their caregivers are understudied in India. We conducted a qualitative study using semi-structured qualitative interviews among treatment-completed DR-TB patients (n = 20) and caregivers (n = 20) in Bengaluru and Hyderabad districts, which represented two different socio-cultural settings in South India. Criterion sampling was used for recruiting the eligible participants who completed treatment with adherence. "Emotional issues and social barriers" were identified to represent a major challenge for patients and caregivers, which occurred acutely after disease diagnosis, characterized by fear and emotional distress due to their perceived loss of life prospects, severity of symptoms, discomfort, and disease denial. Medication intolerance, chronic symptoms, lack of visible signs of treatment progress, loss of weight, and physical concerns caused subsequent fear and distress during the treatment phases for patients along with experiences of stigma. External triggers generated "decisive moments" of hopelessness and life-ending thoughts for patients at the diagnosis and early treatment phase. Medication related challenges included the perceived burden and power of pills which caused emotional distress for patients and intolerance towards caregivers. Pill burden was found as consequential as the side effects of injections. Challenges related to lack of support were another major theme, in which caregivers lacked resources for treatment support and nutrition. Throughout treatment, caregivers and patients expressed concern about a lack of supportive care from family members, sympathy, and intangible social support. Challenges during hospital admission in terms of lack of privacy, quality of services, individual attention, and empathy from health care workers were reported by patients and caregivers. Despite better adherence, DR-TB patients and caregivers experienced considerable emotional and social consequences. Differentiating DR-TB patients and caregivers' issues at different stages of diagnosis and treatment could help improve patient-centered outcomes in India and other high-burden nations.