We report the synthesis and biological evaluation of a small library of 15 functionalized 3-styryl-2-pyrazolines and pyrazoles, derived from curcuminoids, as trypanosomicidal agents. The compounds were prepared via a cyclization reaction between the corresponding curcuminoids and the appropriate hydrazines. All of the derivatives synthesized were investigated for their trypanosomicidal activities. Compounds and showed significant activity against epimastigotes of , with IC values of 5.0 and 4.2 μM, respectively, accompanied by no toxicity to noncancerous mammalian cells. Compound was found to effectively inhibit triosephosphate isomerase. The up to 16-fold higher potency of these derivatives compared with their curcuminoid precursors makes them a promising new family of inhibitors.