Pitaya peels are an underutilized by-product rich in antioxidant phenolics and betalains but highly unstable under environmental and gastrointestinal conditions. This study aimed to produce bioactive-rich particles with improved bioaccessibility by applying ultrasound-assisted extraction (UAE) followed by freeze-drying encapsulation with maltodextrin (MD) and gum Arabic (GA) at different ratios (MD:GA 100:0, 75:25, 50:50, 25:75, 0:100, w/w). A rotatable central composite design (pH 4–8, time 10–50 min) was applied to optimize UAE conditions. Optimum conditions (pH 6.2, 35 min) yielded a pitaya peel extract with TPC 166.85 mg GAE·100 g⁻¹ DW. Although the betalain model was not significant, contents ranged from 30.20 to 51.99 mg·100 g⁻¹ DW across treatments. Particles produced with GA only (G100) had the highest phenolic (316.33 mg GAE∙100 g⁻¹ DW) and betalain (17.58 mg·100 g⁻¹ DW) contents, high solubility (~80%), low hygroscopicity (~11 g H₂O·100 g⁻¹ DW), and amorphous morphology. G100 showed enhanced in vitro bioaccessibility of betalains and phenolics compared to the non-encapsulated extract (p < 0.05). Betalain bioaccessibility decreased in the intestinal phase (~55%), consistent with pH-driven degradation, while phenolic bioaccessibility was higher (~140%). Overall, gum Arabic proved to be an effective carrier for stabilizing pitaya peel bioactives, supporting their valorization into functional food and nutraceutical ingredients.