This study evaluated molecular characteristics that are potentially prognostic in cats with oral squamous cell carcinoma (SCC) that underwent stereotactic radiation therapy (SRT). Survival time (ST) and progression-free interval (PFI) were correlated with mitotic index, histopathological grades, Ki67 and epidermal growth factor receptor expressions, tumour microvascular density (MVD), and tumour oxygen tension (pO2). Median ST and PFI were 106 and 87 days, respectively (n = 20). Overall response rate was 38.5% with rapid improvement of clinical symptoms in many cases. Patients with higher MVD or more keratinized SCC had significantly shorter ST or PFI than patients with lower MVD or less keratinized SCC (P = 0.041 and 0.049, respectively). Females had significantly longer PFI and ST than males (P ≤ 0.016). Acute toxicities were minimal. However, treatment-related complications such as fractured mandible impacted quality of life. In conclusion, SRT alone should be considered as a palliative treatment. MVD and degree of keratinization may be useful prognostic markers.