Background: Progestin-primed ovarian stimulation (PPOS) using dydrogesterone (DYG) has emerged as a potential alternative to conventional gonadotropin-releasing hormone antagonist (GnRH-ant) protocols for controlled ovarian stimulation (COS) cycles. However, the efficacy of the DYG-based PPOS regimen has not been well established. This study aimed to assess the efficacy and safety of the DYG-based PPOS protocol compared to the conventional GnRH-ant regimen during the various stages of COS and intra-cytoplasmic sperm injection (ICSI) procedures. Methods: A randomized controlled trial (RCT) was conducted on 200 infertile women who underwent COS using either the GnRH-ant (n = 100) or PPOS (n = 100) protocols. Generalized linear regression analysis with the appropriate distribution was applied to estimate the adjusted effect of the PPOS protocol on oocyte maturation and retrieval, fertilization, and embryo formation. Results: Both treatment groups had comparable hormonal profiles and procedural characteristics. Compared to the GnRH-ant protocol, the PPOS protocol resulted in an average increase of 1.67 oocytes per retrieval (95% confidence interval (CI): 0.29; 3.04; p = 0.017). The PPOS protocol demonstrated a modest yet significant improvement in the likelihood of oocyte maturation, with an adjusted mean difference of 4.2% (95% CI: 0.4; 8.0; p = 0.03), corresponding to an odds ratio of 1.23 (95% CI: 1.02; 1.47; p = 0.03). The fertilization and embryo development rates (cleavage embryos and blastocysts) were similar between the two protocols. Conclusions: Our findings suggest that the PPOS protocol using DYG offers a slight yet significant advantage over the GnRH-ant protocol regarding the total number of retrieved oocytes and the maturation rate, while maintaining comparable fertilization rates and embryo development outcomes. Clinical Trial Registration: The study has been registered on Visa/ (registration number: NCT06191809).