Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck, with current treatments offering limited improvement in survival outcomes. This has driven interest in natural compounds as potential therapeutic alternatives. Cosmos caudatus (CC), commonly known as “ulam raja,” possesses antioxidant and anticancer properties, but its effects on OSCC remain insufficiently explored. This study aimed to evaluate the cytotoxic effects of CC extract and its impact on TP53/p53 and CD44 expression in an OSCC cell line in vitro. Cells were characterised using immunocytochemistry (ICC) and treated with CC extract (10–80 mg/mL). Cell viability was assessed using the MTT assay, while TP53 and CD44 gene expression were analysed via RT-qPCR. p53 protein levels were quantified using ELISA, and ICC was performed to assess protein expression. Results: CC demonstrated significant cytotoxicity with an IC₅₀ of 58 mg/mL (p < 0.05). Treatment resulted in significant downregulation of TP53/p53 at both gene and protein levels (p < 0.05), alongside increased CD44 mRNA expression but reduced protein staining. CC may therefore have potential as a plant-derived adjunctive therapeutic agent, although further studies are required to elucidate its mechanisms and clinical applicability.