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Trypanosomiasis and leishmaniasis are neglected infections caused by trypanosomatid parasites. The first-line treatments have many adverse effects, high costs, and are prone to resistance development, hence the necessity for new chemotherapeutic options. In line with this, twenty five 4,4′-(arylmethylene)bis(1<i>H</i>-pyrazol-5-ols) derivatives were synthesized and evaluated in vitro for their anti-trypanosomatid activity. Ten and five compounds from this series showed IC₅₀ ≤ 10 µM against the promastigote and the bloodstream stage of <i>Leishmania mexicana</i> and <i>Trypanosoma brucei brucei</i>, respectively. Overall, derivatives with pyrazole rings substituted with electron-withdrawing groups proved more active than those with electron-donating groups. The hits proved moderately selective towards <i>L. mexicana</i> and <i>T. brucei</i> (selectivity index, SI, compared to murine macrophages = 5–26). The exception was one derivative displaying an SI (>111–189) against <i>T. brucei</i> that surpassed, by >6-fold, the selectivity of the clinical drug nifurtimox (SI = 13–28.5). Despite sharing a common scaffold, the hits differed in their mechanism of action, with halogenated derivatives inducing a rapid and marked intracellular oxidative milieu in infective <i>T. brucei</i>. Notably, most of the hits presented better absorption, distribution, metabolism, and excretion (ADME) properties than the reference drugs. Several of the bioactive molecules herein identified represent a promising starting point for further improvement of their trypanosomatid potency and selectivity.