The Potiguar Basin, in Rio Grande do Norte (Northeastern Brazil), has an extensive coastline with a rich diversity of marine sponges that remain poorly explored for their biotechnological potential. In this study, three sponge species—Suberites aurantiacus, Mycale (Zygomycale) angulosa, and Halichondrida—were collected, and a preliminary extraction was then performed to remove the most hydrophobic fraction with n-hexane. The remaining sediment was re-extracted with chloroform and methanol (1:1), and the resulting extracts (ESUB, EMYC, and EHALI, respectively) were analyzed. Chemical characterization using Gas–Liquid Chromatography–Mass Spectrometry (GC/MS) revealed distinct profiles for each genus, with the presence of alcohols, alkaloids, phenolic compounds, and lipids, mainly sterols. ESUB presented 17 identified compounds, EMYC had 15 identified and EHALI showed 15 identified. The antioxidant potential of the extracts was evaluated in vitro using DPPH radical scavenging, copper ion chelation, and total antioxidant capacity (TAC). The EC₅₀ values (mg/mL) for DPPH were 0.05 (ESUB), 0.14 (EMYC), and 0.06 (EHALI), while for copper chelation they were 0.03, 0.034, and 0.026, respectively. Preliminary toxicological assays indicated low toxicity, with IC₅₀ values above 9.6 mg/mL in human erythrocytes and Tenebrio molitor larvae, demonstrating a favorable safety profile for potential therapeutic applications. The study presents a preliminary screening of underexplored species in an equally underexplored region and supports further studies on their bioactive potential.