Ultrasound pretreatment offers a promising approach for improving spice drying efficiency while preserving bioactive compounds. This study explores the optimization of ultrasound pretreatment parameters for black pepper processing, using response surface methodology (RSM) to maximize piperine retention, drying efficiency, and moisture reduction. Compared to traditional one-factor-at-a-time (OFAT) screening, RSM identifies a multi-objective optimal balance that achieves superior results for all three responses. Our optimized conditions (35 kHz, 40 min, 50 °C, 80 W/cm³) achieved 18.64 mg/g DW piperine, a drying time of 444.51 min, and a 9.6% moisture content, demonstrating significant improvements in both bioactive preservation and energy efficiency compared with conventional methods. Compared to control samples requiring 600.69 ± 12.5 min drying time, optimal conditions reduced drying time by 26% to 444.51 min (a net process time reduction of 19%, including a 40 min pretreatment) while achieving the target moisture content (9.6%) and limiting piperine loss to approximately 6% in dried samples. Dual-method validation using UV spectrophotometry and HPLC confirmed model predictions with relative errors below 1%, establishing a consistent UV:HPLC ratio (1:2.12). Multi-analytical characterization revealed that ultrasound-induced cavitation selectively disrupted cellular structures, enhancing mass transfer without significant degradation of piperine’s functional groups. Scanning electron microscopy showed increased porosity and microfractures, while FTIR confirmed preservation of key chemical bonds with minor spectral shifts. The process achieved a five-fold improvement in product consistency (reducing the standard deviation from 0.68 to 0.12 mg/g) compared to conventional drying. These findings demonstrate that optimized ultrasound pretreatment provides a reproducible, scalable, and energy-efficient method for spice processing, supporting industrial adoption where consistent quality and bioactive stability are critical.