Mangiferin, an abundant natural compound in mangoes, has demonstrated notable anti-inflammatory properties across diverse disease models. This review critically examines the recent advancements (primarily post-2020) in elucidating the molecular action mechanisms of mangiferin, emphasizing its role in modulating key signaling pathways such as NF-κB, NLRP3, AMPK, and Nrf2. Its therapeutic potential encompasses a wide range of inflammation-related disorders, including those affecting the bowel, liver, lung, kidney, brain, and cardiovascular system. Additionally, the review addresses the natural and synthetic production of mangiferin, its synergistic effects in combination therapies, strategies for enhancing its bioavailability, and in silico-based predictive analyses. While preclinical data affirm its safety, we identified key gaps for clinical translation: sustainable production, bioavailability optimization, and validation in human trials. This work underscores the unique potential of mangiferin as a next-generation anti-inflammatory therapeutic agent.