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Perceived stigma and psychological distress among tuberculosis (TB) patients may reduce motivation and adherence to prolonged treatment. However, their combined influence on adherence and outcomes among TB patients and household contacts receiving tuberculosis preventive therapy (TPT) remains insufficiently explored in India. The objective is to assess perceived stigma, mental health problems, and their influence on anti-TB treatment (ATT) adherence and outcomes among TB patients and household contacts on TPT in Gujarat using a mixed-methods approach. An explanatory sequential mixed-methods study was conducted among 200 TB patients on ATT and 400 household contacts on TPT. Quantitative data were collected using a sociodemographic proforma, Perceived TB Stigma Scale, Depression Anxiety Stress Scale-21, self-reported adherence, pill counts, and treatment records. Maximum variation sampling was used to select 30 TB patients and 15 household contacts for in-depth interviews. Interviews were conducted and analyzed thematically. Quantitative and qualitative findings were integrated using a joint display approach. High perceived stigma was reported by 67% of TB patients and 45.5% of household contacts. High stigma was associated with higher odds of minor ATT adherence issues (adjusted odds ratio [AOR]: 1.67, 95% CI: 1.04–2.58) and major adherence issues (AOR: 2.31, 95% CI: 1.14–4.69). Treatment success was achieved by 68% of patients. Depression, anxiety, and stress were significantly associated with nonadherence. Qualitative findings revealed themes of shame, discrimination, economic fear, emotional burden, and coping support. TB stigma and psychological distress substantially influence adherence and treatment outcomes. Integrated psychosocial support should be incorporated into TB care.