Direct halogenation of phenolic compounds present in the CH2Cl2 extract of the roots of Arrabidaea brachypoda was investigated to enhance chemodiversity. The approach is based on eco-friendly reactions using NaBr, NaI, and NaCl in aqueous media to generate multiple “unnatural” halogenated natural products from crude extracts. The halogenation reactions, monitored by UHPLC-PDA-ELSD-MS, were optimized to generate mono-, di-, or trihalogenated derivatives. To isolate these compounds, the reactions were scaled up and the halogenated analogues were isolated by semipreparative HPLC-UV and fully characterized by NMR and HR-MS data. All of the original 16 halogenated derivatives were evaluated for their antiparasitic activities against the parasites Leishmania amazonensis and Trypanosoma cruzi. Compounds presenting selective antiparasitic activities against one or both parasites with IC50 values comparable to the reference were identified.