Colorectal cancer (CRC) is a significant health burden globally, with the third highest incidence and the second highest mortality among all types of cancer. Understanding the mechanisms underlying CRC progression is crucial for advancing therapeutic strategies. Organelles are essential components of cells and play a critical role in the initiation and progression of cancer. Over the past decades, numerous studies have demonstrated that mitochondria and the endoplasmic reticulum (ER) can communicate through signaling pathways, thereby regulating cellular homeostasis and function in both normal and cancer cells. This interaction primarily occurs through mitochondria-associated endoplasmic reticulum membranes (MAMs). MAMs, as key nodes in cancer initiation and progression, are also potential vulnerabilities of cancer cells, offering promising opportunities for cancer treatment. Recent research further emphasizes the close association between MAMs and CRC in terms of proliferation, apoptosis, and invasion. To deepen our understanding of the interactions and mechanisms between mitochondria and the ER in CRC, this review, for the first time, synthesizes the research advancements concerning the crosstalk between these organelles in CRC. It innovatively identifies potential targets associated with MAMs, aiming to uncover novel therapeutic strategies for CRC.