Background/Objectives: Rhodesain is a cysteine protease crucial for the life cycle of Trypanosoma brucei rhodesiense, a parasite that causes the lethal form of human African trypanosomiasis. For these reasons, rhodesain is considered an important target for the drug discovery process of novel antitrypanosomal agents. Methods: In the present work, we carried out a combination study of two novel synthetic nitriles, Nitrile 1 and Nitrile 2, with curcumin, the golden multitarget nutraceutical obtained from Curcuma longa L., which we demonstrated to inhibit rhodesain in a non-competitive manner. We calculated the combination index (CI) in both the combination studies by using the Chou and Talalay method. Results: Comparing the CI values of the combinations Nitrile 1 + curcumin and Nitrile 2 + curcumin, we assessed that the inhibitory effect of the combination Nitrile 2 + curcumin against rhodesain was much more potent than that of the other combination. At the IC50 value, in the case of the combination Nitrile 1 + curcumin an additive effect occurred, while in the case of Nitrile 2 + curcumin, we observed a moderate synergism: at 99% of the effect, the synergism induced by the combination Nitrile 2 + curcumin was much stronger than the synergism promoted by the combination Nitrile 1 + curcumin (CI = 0.3843 vs 0.6622, respectively). Conclusions: The co-administration of dipeptide nitriles with curcumin enhances rhodesain inhibition through synergistic effects. Notably, Nitrile 2 + curcumin exhibits a stronger synergy at higher inhibition levels, indicating a greater therapeutic potential.