Powdered Arthrospira platensis (Spirulina) is one of the most valuable nutraceutical products in terms of functionality and food-fortification due to its recognized prebiotic, antioxidant, and immunomodulatory potential. The present study aims to assess the quality of this matrix as a prebiotic after Cold Atmospheric Pressure Plasma (CAPP) processing. CAPP-treated Spirulina samples (1 mg/mL), at effective discharge power of 1.1, 1.7, 2.2 and 3.3 W for 5 min, were used to promote the growth of the probiotics Limosilactobacillus reuteri and Lacticaseibacillus rhamnosus GG. Chicory inulin was used as reference prebiotic material (1 mg/mL). - Microorganisms were inoculated in the different prepared media, and incubated 48 h, at 30 °C, under anaerobic conditions. The probiotics' growth rate on Spirulina (CAPP treated and untreated) dispersions, protein stability and their secondary metabolites production were evaluated. The bacterial growth (>7.0 ± 0.2 log10 cycles) and prebiotic indices of treated Spirulina samples (compared to untreated Spirulina) confirm the prebiotic functionality before and after CAPP processing. The proteomic and metabolomic profiles of the hydrolyzed matrix post-fermentation revealed significant differences in the nutritional values of the final fermented product, depending on the applied CAPP intensity. The present study provides first-time insight into CAPP optimization for increased bioavailability of Spirulina compounds and quality proofed nutraceutical development.