In the present study, we demonstrated that ivermectin suppressed ESCC cell growth, migration and invasion through inducing PAK1 degradation via the proteasome‐dependent signalling pathway, and the conclusion is based on the following effects: (a) Ivermectin greatly inhibited the expression of PAK1 protein in both tested ESCC cell lines and tumour xenografts, but had no obvious effect on PAK1 mRNA level, indicating that ivermectin‐mediated down‐regulation of PAK1 might not be at the transcription level. This evidence concerns the gene PAK1 and esophageal squamous cell carcinoma.