The Caatinga biome, an endemic biome in Brazil with extreme environmental conditions, favors the production of bioactive natural compounds—with a potential antifouling effect—by terrestrial plants. We report antifouling screening of Caatinga plant extracts against marine bacterial biofilm and their toxicity towards non-target organisms. Twelve aqueous plant extracts, collected in the Vale do Catimbau region of PE, Brazil, were employed in different concentrations (0–0.5–1–2–4–8 mg mL−1) in this study. The biofilm and planktonic bacteria inhibition potential were evaluated through flow cytometry and by crystal violet assay. The treatments that showed inhibition of biofilm bacterial density (≥ 80%) and biomass were evaluated for their toxicity. Growth inhibition of the planktonic microalgae, Chaetoceros calcitrans; mortality of the benthic copepod, Nitokra sp.; and mortality and swimming alteration of the planktonic brine shrimp, Artemia salina were used as endpoints. The extracts of Harpochilus neesianus mix and Turnera hermannioides leaves presented ≥ 86% and ≥ 44% inhibition of initial biofouling density and biomass, respectively, without inhibiting marine planktonic bacterial growth, while extracts of Myracrodruon urundeuva leaves showed high antibiotic activity. These extracts were active against marine bacterial biofilms density and biomass and were safe to non-target organisms at lower concentrations. Our study demonstrates the biotechnological potential of plant extracts from Caatinga as an antifouling alternative.