<p>Cisgender (cis) Black women in the USA face high HIV disparities, underscoring the need for effective prevention measures. Although pre-exposure prophylaxis (PrEP) is an effective preventive tool, its use remains limited. This study explored the correlates of PrEP readiness among substance-using cis Black women in Houston, Texas, highlighting its link with PrEP willingness. Using the motivational PrEP cascade as a framework, this cross-sectional secondary analysis, derived from a pilot randomized controlled trial (RCT), explored the relationship between PrEP readiness and willingness and discerned the unique determinants of this relationship. Baseline data included socio-demographics, condomless sex, substance use problems, and PrEP-related factors. Participants were recruited from two hospital emergency departments. Descriptive statistics, logistic regressions, and moderation analyses were conducted (<i>n</i> = 40). Among the 40 participants, 95% were knowledgeable about PrEP, but their readiness levels varied, with only 40% expressing willingness. Participants in Stage 3, or the preparation stage of PrEP readiness, were 1.6 times more likely to adopt PrEP and report a greater frequency of alcohol problems compared to participants in the pre-contemplation stage. Across all stages of readiness, participants’ PrEP willingness increased the most in Stage 3, peaking at 83%. This study highlights the importance of PrEP readiness, especially the pivotal role of the third preparation stage, in the likelihood of substance-using cis Black women expressing a willingness to adopt PrEP, with frequent alcohol use emerging as a pivotal determinant. This study advocates for tailored PrEP interventions exploring readiness and motivation and more comprehensive behavioral risk assessments for Black women.</p>