Oral squamous cell carcinoma (OSCC) progresses from epithelial cell proliferation to malignancy. Given the higher proportion of male patients compared to female patients, the androgen signaling pathway is believed to play a significant role in promoting epithelial cell proliferation. However, the underlying molecular mechanisms remain unclear. Here, we identified RBAP48 as a novel androgen receptor (AR) co-activator in OSCC cells. Our results show that RBAP48 was highly expressed in OSCC tumor tissues from patients with a poor prognosis. Further, RBAP48 knockdown decreased genome-wide oncogene transcription. RBAP48 and AR interacted to activate CCND1 and RAB31 transcription, and upregulated RELA and CCNE1 mRNA expression through an AR-independent pathway. Additionally, RBAP48 promoted OSCC cell proliferation and was involved in the cellular response to drugs and external compounds in vitro, ultimately driving cancer progression. Our results indicate that RBAP48 is a novel oncogene and a promising target for predicting and treating OSCC progression.