Introduction: Pineapple processing generates substantial by-products (crown, core, and shell) rich in bioactive compounds, yet their valorization remains underexplored. This study aimed to optimize ultrasonic-assisted extraction parameters to maximize phenolic content and antioxidant activity from pineapple by-products. Methods: A central composite design (30 runs) was employed to evaluate five factors; pineapple by-product (crown, core, shell), extraction technique (ultrasonic bath vs. probe), ethanol concentration (0–100%), ultrasonic power (40–80%), and extraction time (4–20 min). Responses included total polyphenol content (TPC), ferric-reducing antioxidant power (FRAP), DPPH scavenging activity, and ascorbic acid content (AAC). Predictive and optimization models were also developed and validated. Results: Extraction efficiency varied significantly across by-products. Shell extracts exhibited the highest TPC (up to 7.59 gallic acid equivalents/g dw) and FRAP (up to 102.06 μM ascorbic acid equivalents/g dw), and DPPH scavenging (30.26 μM ascorbic acid equivalents/g dw). Crown parts peaked AAC (up to 546.72 mg/g dw). Ultrasonication probe assisted extraction (UPAE) generally outperformed bath (UBAE) for phenolic recovery. Optimal conditions varied by target compound: shell with 0% ethanol, 40% power, 20 min (UPAE) yielded maximum TPC; crown with 50% ethanol, 40% power, 12 min (UPAE) maximized DPPH activity. Predictive models showed good correlation with experimental data. Conclusion: Pineapple by-products represent valuable sources of natural antioxidants, with extraction efficiency highly dependent on processing parameters. These findings support sustainable valorization of agro-industrial waste for nutraceutical and food applications.