Background: Chemotherapeutic approaches to the control of HPV infection suffer from a lack of specificity. For most existing HPV inhibitors, the weak antiviral effects observed in cellular assays suggest that further improvements in selecting targets, in drug potency, and in bioavailability and cell uptake are required. Objective: To synthesize novel 1,3-oxazole derivatives and define their antiviral activities against the human papillomavirus (HPV) in vitro. Methods: Determination of transient replication of an HPV-11 in transfected HEK293 cells, and HPV-18 DNA amplification in an organotypic squamous epithelial raft culture of primary human keratinocytes (PHKs), and cytotoxicity assays were used. Results: Bioassays showed that the synthesized compounds 2, 4, 5, and 9 exhibited potent antiviral activity against low-risk HPV-11 (IC50 = 1.7–9.6 μM) in a transient DNA replication assay and exhibited low cytotoxicity in HEK293 cells compared to cidofovir (CDV), antiviral agent in clinical use. Selectivity indices of compounds 4 and 5 were 20–40 times greater than that of CDV. However, compounds 4 and 9 did not exhibit a significant antiviral effect against high-risk HPV-18 infections in organotypic epithelial raft cultures. Although prophylactic HPV vaccines are now available to protect against primary infections by the seven genotypes most commonly found in cervical, penile, anal and oro-pharyngeal cancers (HPV16, 18, 31, 33, 45, 52, and 58) and two genotypes (HPV6 and 11) that cause benign anogenital warts and laryngeal papillomas, they do not protect against infections by other HPV types. Moreover, individuals already infected with HPV will not benefit from the vaccines. Thus, the need for antiviral agents to treat HPV-associated diseases remains great, but few options currently exist. Conclusions: We show that substituted 1,3-oxazole derivatives are a promising structure class of chemical compounds for the development of antiviral drugs against HPV lesions.