This study synthesises global evidence on the role of biology-mathematics (Bio-Mat) integration in developing 21st-century competencies, with particular attention to its implications for the Indonesian Merdeka Curriculum context, through a systematic literature review (SLR) following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) protocol. Given the scarcity of Bio-Mat-specific research in Indonesia, this review intentionally adopts a global scope, drawing on studies from Asia, North America, Europe, Africa, and global comparative contexts, to synthesize the best available international evidence, which is then critically examined for its transferability and relevance to the Indonesian educational context, particularly within the framework of the Merdeka Curriculum. Relevant studies were retrieved from ERIC and Scopus for the 2017–2026 period, and 72 eligible studies were included for final analysis. Results indicate that Bio-Mat integration is most effectively implemented through Project-Based Learning (PjBL) models centred on mathematical modelling of biological phenomena, yielding the highest effect sizes (g ≈ 0.87–0.88) across critical thinking, problem-solving, and collaboration outcomes. Mathematical Modelling demonstrated the greatest contribution to conceptual understanding (g = 0.95). Findings further reveal that Bio-Mat integration significantly strengthens students' numeracy literacy and aligns directly with the eight graduate dimensions of deep learning , keimanan/ketakwaan, kewargaan, penalaran kritis, kreativitas, kolaborasi, kemandirian, kesehatan, and komunikasi, as mandated by the Merdeka Curriculum. The review also identifies major implementation barriers, particularly teacher training gaps, limited resources, and uneven technological access, and offers evidence-based recommendations for curriculum designers and educators across Indonesian secondary and tertiary educational contexts.