Aggressive cancers in the epithelial-to-mesenchymal transition (EMT) phase are characterized by loss of cell adhesion, repression of E-cadherin, and increased cell mobility. Non-small cell lung cancer (NSCLC) differs in basal level of E-cadherin; predominantly exhibiting silenced expression due to epigenetic-related modifications. Accordingly, effective treatments are needed to modulate these epigenetic events that in turn can positively regulate E-cadherin levels. Herein, we investigated silibinin, a natural flavonolignan with anticancer efficacy against lung cancer, either alone or in combination with epigenetic therapies to modulate E-cadherin expression in a panel of NSCLC cell lines. Silibinin combined with HDAC inhibitor Trichostatin A [TSA; 7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienamide] or DNMT inhibitor 5'-Aza-deoxycytidine (Aza) significantly restored E-cadherin levels in NSCLC cells harboring epigenetically silenced E-cadherin expression. These combination treatments also strongly decreased the invasion/migration of these cells, which further emphasized the biologic significance of E-cadherin restoration. Treatment of NSCLC cells, with basal E-cadherin levels, by silibinin further increased the E-cadherin expression and inhibited their migratory and invasive potential. Additional studies showed that silibinin alone as well as in combination with TSA or Aza downmodulate the expression of Zeb1, which is a major transcriptional repressor of E-cadherin. Overall these findings demonstrate the potential of combinatorial treatments of silibinin with HDAC or DNMT inhibitor to modulate EMT events in NSCLC cell lines, leading to a significant inhibition in their migratory and invasive potentials. These results are highly significant, since loss of E-cadherin and metastatic spread of the disease via EMT is associated with poor prognosis and high mortalities in NSCLC.