Cervical carcinoma is the third most common cause of cancer in women with a significant challenge in clinical treatment. Human papillomavirus (HPV) is strongly responsible for cervical carcinoma. Here, we show the increased expression level of heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) in HPV-associated cervical cancer cells including HeLa, Caski, and SiHa cells, especially in HeLa cells. We provide the evidence that the expression of HNRNPA1 is closely related to HeLa cell proliferation, invasion, and migration. Emerging evidence show that histone modifications account for gene expression. Moreover, our results indicate that HNRNPA1 could be regulated by p300 through p300-mediated lysine crotonylation. Inhibition of p300 downregulated both the lysine crotonylation level and the HNRNPA1 expression. And p300-mediated lysine crotonylation participates in the regulation of HNRNPA1 on HeLa cell proliferation, invasion, and migration. Collectively, our study uncovers that p300-mediated lysine crotonylation enhances expression of HNRNPA1 to promote the proliferation, invasion, and migration of HeLa cells. © 2020 Xuesong Han et al.