BackgroundDespite having an effective community-based Directly Observed Therapy Short-course (DOTS) strategy for tuberculosis (TB) care, treatment adherence has been a major challenge in many developing countries including Ghana. Poor adherence results in discontinuity of treatment and leads to adverse treatment outcomes which pose an increased risk of drug resistance. This study explored barriers to TB treatment adherence and recommended potential patient-centered strategies to improve treatment adherence in two high-burden TB settings in the Ashanti region of Ghana.MethodsThe study was conducted among TB patients who defaulted on treatment in the Obuasi Municipal and Obuasi East districts in the Ashanti region. A qualitative phenomenology approach was used to explore the barriers to TB treatment adherence. Purposive sampling was adopted to select study participants with different sociodemographic backgrounds and experiences with TB care. Eligible participants were selected by reviewing the medical records of patients from health facility TB registers (2019–2021). Sixty-one (61) TB patients met the eligibility criteria and were contacted via phone call. Out of the 61 patients, 20 were successfully reached and consented to participate. In-depth interviews were conducted with participants using a semi-structured interview guide. All interviews were audio recorded and transcribed verbatim. The transcripts were imported into Atlas.ti version 8.4 software and analyzed using thematic content analysis.ResultsFood insecurity, cost of transportation to the treatment center, lack of family support, income insecurity, long distance to the treatment center, insufficient knowledge about TB, side effect of drugs, improvement in health after the intensive phase of the treatment regimen, and difficulty in accessing public transportation were the main co-occurring barriers to treatment adherence among the TB patients.ConclusionThe main barriers to TB treatment adherence identified in this study reveal major implementation gaps in the TB programme including gaps related to social support, food security, income security, knowledge, and proximity to treatment centers. Hence, to improve treatment adherence there is a need for the government and the National Tuberculosis Programme (NTP) to collaborate with different sectors to provide comprehensive health education, social and financial support as well as food aid to TB patients.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12889-023-16259-6.