Colorectal cancer (CRC) remains the second most lethal cancer worldwide, with incidence rates expected to rise substantially by 2040. Although biomarker-driven therapies have improved treatment, responses to standard chemotherapeutics, such as 5-fluorouracil (5-FU), oxaliplatin, and irinotecan, vary considerably. This clinical heterogeneity emphasizes the urgent need for novel biomarkers that can guide therapeutic decisions and overcome chemoresistance. microRNAs (miRNAs) have emerged as key post-transcriptional regulators that critically influence chemotherapy responses. miRNAs orchestrate post-transcriptional gene regulation and modulate diverse pathways linked to chemoresistance. They influence drug transport by regulating ABC transporters and affect metabolic enzymes like thymidylate synthase (TYMS). These activities shape responses to standard CRC chemotherapy agents. Furthermore, miRNAs can regulate the epithelial-mesenchymal transition (EMT). The miR-200 family (e.g., miR-200c and miR-141) can reverse EMT phenotypes, restoring chemosensitivity. Additionally, miRNAs like miR-19a and miR-625-3p show predictive value for chemotherapy outcomes. Despite these promising findings, the clinical translation of miRNA-based biomarkers faces challenges, including methodological inconsistencies and the dynamic nature of miRNA expression, influenced by the tumor microenvironment. This review highlights the critical role of miRNAs in elucidating chemoresistance mechanisms and their promise as biomarkers and therapeutic targets in CRC, paving the way for a new era of precision oncology.