The intricate interplay between the human microbiota and the immune system has garnered significant attention in recent years, particularly concerning its implications in cancer biology. Macrophages, pivotal players in the tumor microenvironment (TME), exhibit diverse phenotypes that can either promote tumor progression or inhibit it. This review explores the multifaceted role of the microbiota in modulating macrophage polarization within the TME. We highlight recent findings that demonstrate how specific microbial communities influence macrophage behavior through metabolic pathways, immune signaling, and epigenetic modifications. Furthermore, we discuss the therapeutic potential of manipulating the microbiota to reprogram macrophage phenotypes, thereby enhancing antitumor immunity. By integrating insights from microbiology, immunology, and oncology, this article aims to provide a comprehensive overview of the microbiota’s impact on macrophage dynamics in cancer, paving the way for innovative therapeutic strategies that harness this relationship for improved clinical outcomes.