The aims of this paper are to inform audit practice and academia about the potential behavioral challenges to the application of auditors’ professional skepticism when using audit data analytics (ADA) and to discuss future research opportunities. This is accomplished by reviewing relevant audit research and discussing the potential challenges from five perspectives, including auditors’ attitudes toward ADA, data characteristics, anomalies identified by ADA, auditors’ mindsets, and social contexts and interactions involved in ADA practice. Although applying ADA brings many benefits to audit practice, they simultaneously raise many challenges to the application of appropriate levels of auditor professional skepticism. Being aware of and prepared for those potential behavioral challenges is critical to maximize the benefits of ADA to professional skepticism and ultimately audit quality.