Abstract: Distant metastasis and dissemination are the leading contributors to colorectal cancer (CRC) death. The underlying biomechanisms by which the SLC2A3 promotes CRC aggression still need to be comprehensively clarified. Data on SLC2A3 expression in normal and tumor tissues from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases were analyzed. Prognostic values were assessed using a Kaplan–Meier analysis. The construction of overexpressed and knockout cell lines of SLC2A3 was performed using the CRISPR-Cas9 system. Biological functions, including migration and invasion, were detected using a transwell assay. SLC2A3 subcellular location was determined using immunofluorescence staining. Signaling pathway analysis was accomplished by RNA sequencing and GO pathway enrichment. SLC2A3 downstream effectors were validated via qRT-PCR and Western blotting after gene interference and overexpression. Furthermore, SLC2A3 and related proteins in CRC tissues were detected by immunohistochemistry. The in vivo mouse xenograft model was performed to assess distant lung metastasis. Finally, the clinicopathological features, prognostic values, and correlations between SLC2A3 and associated molecules were analyzed using the Chi-square test, Spearman’s rho model, and Kaplan–Meier analysis. The results showed that SLC2A3 was markedly up-regulated in CRC samples and linked to adverse outcomes. We also demonstrated that SLC2A3 promotes CRC migration and invasion in vitro, which is involved in pathways associated with cancer and cytokine–cytokine receptor interaction. We confirmed that SLC2A3 accelerates CRC migration and invasion by activating the YAP-1/PDGFB axis. Furthermore, we validated that PDGFB facilitates CRC migration and invasion. Moreover, the in vivo mouse xenograft studies confirmed that SLC2A3 promoted CRC cells distant lung metastasis by activating the YAP-1/PDGFB axis. High SLC2A3, YAP-1, and PDGFB expressions in the CRC tissues were significantly correlated with lymph node metastasis, nervous invasion, lymphovascular invasion, distant metastasis, and pTNM stage, respectively. There was a correlation with the expression of SLC2A3, YAP-1, and PDGFB in CRC tissues, and high expression of them was a hazard factor for CRC. Taken together, SLC2A3 serves as an oncogene to promote CRC aggression and is associated with adverse prognosis through positively simulating the YAP-1/PDGFB axis. It may be used as a potential biomarker of CRC prognosis and a prospective target for CRC treatment.