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Background: The COVID-19 pandemic disrupted healthcare services worldwide, potentially worsening outcomes for individuals with chronic infectious diseases, including tuberculosis (TB) and HIV.Objective: To identify factors associated with mortality among patients with TB–HIV co-infection, and to assess the impact of the COVID-19 pandemic on these outcomes.Methods: Methods: We analyzed 3,352 TB-HIV cases treated at a referral center in Amazonas, Brazil (2014-2022). Two case-control analyses compared TB-related and non-TB-related deaths with cured TB patients. Multivariate logistic regression was used to identify independent risk factorsResults: In TB-related death group, predictors included diagnosis during the COVID-19 pandemic, rural residence, disseminated TB, prior TB treatment, CD4+ <200, and HAART initiation at or after TB diagnosis. Non-TB deaths were associated with age >60, homelessness, disseminated TB, prior treatment, low CD4+, high viral load, and delayed or absent HAART. Both groups reflected advanced disease, immunosuppression, and poor treatment access.Conclusions: The pandemic increased TB-related mortality but not non-TB deaths. Mortality was also driven by disease severity, delayed care, and social vulnerability, with rural residence highlighting healthcare barriers. Tackling the TB–HIV–COVID-19 syndemic demands integrated, context-sensitive strategies targeting biological, social, and structural determinants to reduce mortality and improve outcomes in high-burden, resource-limited settings.