Background: Screening for harmful alcohol use (HAU) is standard in clinical settings; however, self-reports of the quantity/frequency of use are often inconsistent with population survey data and objective assessment. Inaccuracies of self-reported alcohol use prompt exploration of patients’ reluctance to share this information with their health care providers. Objectives: The purpose of this article is to identify the assumptions and biases that affect screening and brief interventions for HAU. Method: A total of 22 research articles were selected for a systematic review of the literature. The studies included prospective and retrospective studies, randomized controlled trials, case studies, and quantitative and qualitative research from 2015 to 2021. Results: This systematic review identified alcohol health literacy, the inherent bias of surveys and screening tools, stigma, avoidance bias, and the normalization/villainization of alcohol use as contributors to the assumptions and biases that affect screening and brief interventions for HAU. Conclusions: Exploring these assumptions and biases presents opportunities to develop strategies that promote positive change.