Background: High responders are characterized by a large number of retrieved oocytes and/or a high level of estradiol on the day of administration of human chorionic gonadotropin. There is controversy in the literature regarding live birth rates from fresh day-5 single blastocyst transfer (day-5 SBT) compared to cleavage-stage fresh day-3 embryo transfer (day-3 ET) in high responders. The aim of this study was therefore to compare reproductive outcomes between day-5 SBT and day-3 ET using high-quality embryos and gonadotropin-releasing hormone (GnRH) antagonist protocols in high responders undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Methods: This was a single-center retrospective study of 282 high responders who underwent fresh day-5 SBT (day-5 SBT group, n = 142) or two cleavage-stage fresh day-3 embryo transfer (day-3 ET group, n = 140) between 2015 and 2019. Results: No significant differences were observed between the day-5 SBT and day-3 ET groups in terms of clinical pregnancy rate (51.41% vs. 59.29%, p = 0.183) or live birth rate (41.55% vs. 52.86%, p = 0.057). The incidence of multiple pregnancy (1.37% vs. 36.14%) and of low birth weight (5.00% vs. 32.26%) were significantly less frequent in the day-5 SBT group than in the day-3 ET group (p 0.001 and p 0.001, respectively). Conclusions: SBT may be the preferred choice for high-quality embryos in high responders undergoing IVF/ICSI during GnRH antagonist cycles with fresh embryo transfers. This is due to the lower incidence of obstetric complications compared to day-3 ET, although the clinical outcomes for the two groups are comparable.