NSD3 (WHSC1L1) is a protein lysine methyltransferase that is recurrently amplified (8p11.23) in several cancer types, and its upregulation is involved in tumor cell proliferation, metastasis, and epithelial-mesenchymal transition (EMT). We aimed to evaluate its potential function as an oncogenic force in colorectal cancer (CRC), and to elucidate relevant mechanisms of its oncogenic activity. NSD3 levels were analyzed in human CRC and adjacent normal tissues or cells by Western blot analysis and RT-qPCR. Expression levels of the proteins were detected by Western blot analysis and RT-qPCR. NSD3 was significantly upregulated in both CRC tissues and cell lines. Knockdown of NSD3 expression resulted in significant decreases in CRC cell proliferation, migration, and EMT process marker proteins vimentin, simultaneously reducing E-cadherin and N-cadherin expression. The opposite results were observed when NSD3 was overexpressed. Additionally, overexpressing of NSD3 dramatically activated the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and enhanced actin-capping protein (CAPG) expression. Furthermore, the proliferation and migration abilities evidently facilitated by pcDNA3.1(+) expression vector containing full-length CDS of NSD3 (pcDNA3.1(+)-NSD3, or NSD3) were partially decreased after incubation with ERK1/2 signaling pathway inhibitor (PD98059) and/or specific siRNA against CAPG (siCAPG) in SW480 and HT-29 CRC cells. NSD3 overexpression stimulated CRC cell proliferation and migration through targeting the ERK1/2 signaling pathway and downstream CAPG. Thus, NSD3 could serve as a promising target for anticancer drug development for patients with CRC.