Mental health stigma, encompassing negative attitudes and behaviors toward individuals with mental illnesses, remains a global barrier to treatment and social inclusion. This systematic review synthesizes peer-reviewed studies from 2015 to 2024 to examine cultural, social, and systemic drivers of stigma across Western, Asian, African, Latin American, and Middle Eastern contexts. Using thematic analysis, we identified universal stigma drivers—lack of awareness, fear, and misinformation—and region-specific influences, such as collectivism in Asia and spiritual beliefs in Africa. Stigma consistently reduces help-seeking and treatment adherence, with marginalized groups facing amplified barriers due to gender, race, and socioeconomic status. Successful interventions, including the UK’s Time to Change and Uganda’s peer support programs, highlight the value of culturally tailored approaches. Healthcare systems and policies, like the WHO’s Mental Health Action Plan, play critical roles in addressing stigma. Future research should focus on understudied regions (e.g., Central Asia) and populations (e.g., refugees), leveraging digital platforms and cross-cultural collaborations. This review calls for evidence-based, culturally sensitive strategies to reduce stigma and enhance global mental health outcomes.