In 2021, the Centers for Disease Control and Prevention (CDC) proposed updated clinical practice guidelines for Pre-Exposure Prophylaxis (PrEP), marking a significant shift from risk-based screening to discussing PrEP with all sexually active adults. To ensure widespread adoption of new guidelines, this commentary posits that intentional de-implementation of the previous CDC guidelines is necessary to facilitate the adoption, implementation, and sustainment of new guidelines. Based on a review of the literature, the authors leveraged implementation science frameworks (i.e., CFIR, ERIC taxonomy, and RE-AIM) to map theoretical determinants, corresponding strategies, and outcomes in the context of de-implementing previous CDC guidelines for PrEP and simultaneously implementing the new guidelines. Potential barriers identified included resource constraints, staff capability, and structural characteristics of organizations that may impede de-implementation efforts. Potential facilitators included provider motivation and incentive systems that encourage providers to discuss PrEP with sexually active clients. Strategies like normalizing PrEP education and services, workflow redesign, and task-shifting could tackle workforce challenges. These strategies could aid in phasing out old guidelines, implementing new guidelines, increasing PrEP referrals, and reducing HIV incidence. Phasing out previous PrEP guidelines demands intentional (de-)implementation to enhance universal HIV prevention efforts and advance national plans for Ending the HIV Epidemic.