Abstract Background Multidrug-resistant tuberculosis (MDR-TB) is a serious phenomenon on a global scale that can worsen with the COVID-19 pandemic. The study aimed to understand the perceptions of health professionals about MDR-TB, their strategies to ensure adherence to treatment and their challenges in the context of the COVID-19 pandemic in a priority municipality for disease control. Methods We conducted a qualitative study and recruited 14 health providers (four doctors, three nurses, three nursing technicians, three nursing assistants and a social worker) working in a city in the state of São Paulo, Brazil. Remote semi-structured interviews were conducted with the participants. For data analysis, the thematic content analysis technique was applied according to the study’s theoretical framework. Results The study revealed the causes of MDR-TB are associated with poverty, vulnerability, and social risk. A pre-judgement from the providers was observed, namely, all patients do not adhere due their resistance and association with drug abuse or alcoholism. The study also observed difficulty among health providers in helping patients reconstruct and reframe their life projects under a care perspective, which would strengthen adherence. Other issues that weakened adherence were the cuts in social protection and the benefits really necessary to the patients and a challenge for the providers manage that. The participants revealed that their actions were impacted by the pandemic and insecurity and fear manifested by patients after acquiring COVID-19. For alleviating this, medical appointments by telephone, delivery of medicine in the homes of patients and visits by health professionals once per week were provided. Conclusion The study advances knowledge by highlighting the challenges faced by the health system with the adherence of patients with MDR-TB in a context aggravated by the pandemic. An improvement in DOT is really necessary to help the patients reframe their lives without prejudices, face their fears and insecurity, recover their self-esteem and motivate in concluding their treatment.