Colorectal cancer (CRC) is a significant global health challenge, marked by varying incidence and mortality rates across different regions. The pathogenesis of CRC involves multiple stages, including initiation, promotion, progression, and metastasis, influenced by genetic and epigenetic factors. The chaperone protein glucose-regulated protein 78 (GRP78), crucial in regulating the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, plays a pivotal role in CRC pathogenesis. This review discusses the expression profile of GRP78 in CRC, highlighting its potential as a prognostic biomarker and its role in modulating the cellular mechanisms of CRC, including ER response regulation, cell proliferation, migration and invasion. The complex molecular interactions of GRP78 with key signaling pathways such as protein kinase B (Akt), Wnt, protein kinase R-like ER kinase (PERK), vascular endothelial growth factor (VEGF), and Kirsten rat sarcoma virus (Kras) are explored, elucidating its contributions to tumor survival, proliferation, invasion, and chemoresistance. GRP78's involvement in autophagy, glycolysis, and immune regulation further underscores its importance in CRC progression. The review also covers the therapeutic potential of targeting GRP78 in CRC, examining various natural products like curcumin, epigallocatechin gallate (EGCG), and aloe-emodin, which modulate GRP78 expression and activity. Additionally, GRP78's role in mediating resistance to chemotherapeutic agents like 5-fluorouracil (5-FU) and oxaliplatin is discussed, emphasizing its significance in the development of resistance mechanisms in CRC. In conclusion, GRP78 emerges as a central player in CRC pathogenesis and a promising target for therapeutic interventions aimed at improving treatment outcomes and overcoming chemoresistance in colorectal cancer.