The incidence of early-onset colorectal cancer (CRC) is rising steadily alongside traditional late-onset disease, yet the pathophysiological mechanisms distinguishing these two entities remain largely elusive. Herein, we address this knowledge gap by examining the distinctive properties of P-selectin glycoprotein ligand (PSGL)-1 within the CRC landscape. Given that both early- and late-onset CRC are underpinned by chronic gut inflammation, the potential role of PSGL-1 in this context warrants close investigation. First, we synthesize current evidence on the contributions of PSGL-1 to CRC pathogenesis and propose its function as a molecular bridge between early- and late-onset disease forms. Second, we explore the mechanistic links connecting PSGL-1 to established protumorigenic pathways and to the gut microbiome, reinforcing its emerging significance in CRC development. Finally, by offering deeper insights into the putative roles of PSGL-1 in promoting CRC, we inform new directions for clinical and therapeutic strategies centered on PSGL-1-directed investigation.