Dysregulation of epidermal growth factor receptor (EGFR) signaling is responsible for the resistance to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, and is thereby associated with the progression of tumors in non‑small cell lung cancers (NSCLCs). Immunoblotting results revealed that geranylgeranyl transferase 1 inhibitor (GGTI)‑298, a geranylgeranyl transferase 1 inhibitor with potential antitumor effects, effectively inhibited the phosphorylation of EGFR and its downstream target protein kinase B (AKT). A combination of gefitinib and GGTI‑298 amplified the inhibition of the EGFR‑AKT signaling pathway. In addition, GGTI‑298 treatment produced a synergistic effect on the inhibition of proliferation as indicated by the combination index values of <1 when combined with gefitinib in the NSCLC cell lines HCC827 and A549. These synergistic effects were also observed to induce apoptosis and migration inhibition. Further mechanistic studies demonstrated that GGTI‑298 inhibited the activity of Ras homolog family member A (RhoA), and downregulation of RhoA with small interfering RNA impaired the phosphorylation of EGFR, which suggested that EGFR inhibition by GGTI‑298 may be exerted mainly through RhoA mediation. These results presented a novel, promising therapeutic strategy involving a combination of two drugs for targeting EGFR signaling in lung cancer.