Crescentia alata is valued in traditional medicine for its anti-inflammatory and antimicrobial properties. However, research on its phytochemical composition and bioactivity is scarce. Phenolic compounds are of pharmacological interest because they reduce oxidative stress and inflammation. This study aimed to optimize the pressurized liquid extraction of phenolic compounds to enhance the cellular antioxidant activity of the fruit extract. Response Surface Methodology with a Box–Behnken Design was used. Three variables were evaluated at three levels: temperature (25, 37.5, and 50 °C), pressure (10, 30, and 50 bar), and time (10, 20, and 30 min). The effect of these variables was monitored on the total phenolic content, total flavonoid content, and the percentage of inhibition of reactive oxygen species. The optimal extraction conditions were 40.98 °C, 29.52 bar, and 16.89 min, which yielded a TPC of 28.27 mg GAE/g DW, TFC of 19.08 mg QE/g DW, and 72.05% ROS inhibition. This methodology proved to be effective for optimizing the extraction of phenolic compounds and revealed the influence of extraction conditions on their biological activity.