Despite the advances of therapeutic approaches, morbidity and mortality rate of oral squamous cell carcinoma (OSCC) have not improved significantly during the last 30 years. Photodynamic therapy (PDT) represents a potential treatment modality for locally recurrent OSCC. However, treatment resistance attributed to PDT-induced epidermal growth factor receptor (EGFR) up-regulation was reported. Here, we showed that vandetanib, a multi-target tyrosine kinase inhibitor that inhibits EGFR and vascular endothelial growth factor receptor-2 (VEGFR-2) enhance the efficacy of PDT. First, we observed increased cytotoxicity in the combinatorial treatment that is attributed to impaired DNA double strand break (DSB) repair. We revealed significant down-regulation DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression to be the downstream target following inhibition of nuclear EGFR accumulation, therefore impairing non-homologous end-joining (NHEJ) following PDT. Next, the combinatorial treatment-mediated tumour vasculature shutdown and normalisation, coupled with reduction of PDT-induced EGFR activation corresponded to the most pronounced tumour growth delay in vivo. Interestingly, we observed the restoration of tumour cell proliferation and vascularisation, coupled with ERK1/2 activation in the recurrent tumours post-vandetanib+PDT treatment. This corroborated the importance of the modulation of the tumour microenvironment for the observed synergistic efficacy of vandetanib+PDT combinatorial treatment. Collectively, our data suggests that vandetanib works synergistically with PDT through the impairment of EGFR-dependent DNA repair machinery and modulation of tumour microenvironment.