Pomegranate (Punica granatum L.) fruits are important sources of vitamins and minerals and widely used in the dietary supplement industry. An aqueous extract of its leathery exocarp (LEP) was obtained by a solid-phase micro-extraction method. The antifungal activity was examined against the phytopathogenic fungi, Fusarium oxysporum, Phytophthora cinnamomi, Penicillium digitatum and Botrytis cinerea, and the antibacterial activity was evaluated against Escherichia coli, Xanthomonas campestris,Bacillus megaterium and Clavibacter michiganensis. The antimicrobial assays showed, in some cases, a promising antimicrobial effect compared to the synthetic drugs. The possible anti-acetylcholinesterase and antioxidant activities of the LEP extract were investigated by the Ellman’s assay and 2,2-diphenyl-1-picrylhydrazyl (DPPH) test, respectively, and their results showed that the LEP extract has an effective anti-acetylcholinesterase inhibitory effect and an antioxidant activity. Thus, the LEP extract could be valid as a candidate for further studies on the use of pomegranate in neurodegenerative diseases as a food preservative and a suitable substitute to control several phytopathogens.