Objective To investigate the molecular mechanism by which HMGA2 participates in the TGF-β/Smad pathway in the regulation of the proliferation, aggression, and metastasis of laryngeal cancer. Methods shRNA transfection was used to construct the HMGA2 knockdown laryngeal cancer TU686 cell model, and subcutaneous transplantation tumor model and tail vein metastasis tumor model were established in nude mice. Western blot was conducted to detect the expression of HMGA2 and TGF-β/Smad pathway-related molecules in cells and tumor tissues. Results The proliferation, invasion, and metastasis of TU686 cells with HMGA2 knockdown decreased. The expression of TGF-β, Smad2, Smad3, and phosphorylated Smad2/3 protein also decreased. TGF-β1 stimulation of the TGF-β/Smad pathway could partially offset the antitumor effect caused by HMGA2 knockdown. Through in vitro experiments, we determined that low expression of HMGA2 significantly inhibited the growth of subcutaneously transplanted tumors, and TGF-β1 stimulation of the TGF-β/Smad pathway reduced the tumor-inhibitory effect resulting from the low expression of HMGA2. In tail vein metastases of nude mice, E-cadherin expression was elevated but N-cadherin expression was reduced in the HMGA2 knockdown group, suggesting that HMGA2 could inhibit the progression of EMT. After TGF-β1 stimulated the TGF-β/Smad pathway, the EMT effect due to HMGA2 knockdown was lessened. Conclusion HMGA2 may promote the proliferation, invasion, and metastasis of laryngeal cancer by upregulating the TGF-β/Smad signaling pathway.