Tuberculosis (TB) and psychiatric illnesses frequently coexist, creating significant challenges in diagnosis, treatment adherence, and overall patient outcomes. Individuals with psychiatric disorders are at increased risk of TB due to shared biological, psychological, and socioeconomic vulnerabilities. At the same time, TB itself can worsen mental health through stigma, prolonged treatment, and social isolation. The coexistence of these conditions is further complicated by poor treatment adherence, cognitive impairment, substance use, social disadvantage, and drug–drug interactions between anti-tubercular and psychotropic medications necessitating careful therapeutic monitoring. Integrated care models that incorporate multidisciplinary collaboration, mental health screening, psychoeducation, nursing support, telepsychiatry, and patient-centric interventions are essential to improving outcomes. Addressing stigma, financial barriers, and social determinants of health can further enhance adherence and quality of life. A holistic and coordinated approach is therefore crucial for optimizing treatment outcomes in patients with comorbid TB and psychiatric illnesses.