Background/Objectives: Leishmaniases are a group of neglected tropical diseases that have been overlooked, and new treatments are needed. This is because the parasites that cause it, from the Leishmania genus, have become drug-resistant, and current medications can be toxic. In this regard, arylidenehydrazinyl thiazoles emerge as a potential scaffold for creating new, effective drug candidates to combat this disease. Methods: Here, we report the synthesis of a series of arylidenehydrazinyl thiazole carboxylates (3a–m, 13 examples, 66–78%) using a simple cost-effective strategy via cyclization of aryl-substituted thiosemicarbazones and ethyl-2-chloro-3-oxobutanoate in an equimolar mixture. These compounds were investigated for their promising bioactive properties. Results: All compounds were fully characterized using spectroscopic techniques (¹H-, ¹³C-NMR, FTIR spectroscopy, and HRMS) to confirm their purity and identity. These arylidenehydrazinyl thiazole carboxylates have been tested for their cytotoxicity against promastigote and intracellular amastigote forms of Leishmania amazonensis (IFLA/BR/1967/PH8) and the NIH/3T3 mouse fibroblast cell lines and their potential interaction with Leishmania trypanothione synthetase was explored through in silico molecular docking studies. Conclusions: The compounds showed little or no cytotoxicity against NIH/3T3 fibroblasts, compounds 3a, 3d and 3m showed low cytotoxicity to promastigote forms, but compounds 3b, 3c, 3h and 3m showed activity against amastigotes (IC₅₀ = 15.92 µM for 3m) at the tested concentrations. In silico molecular docking studies have been deployed to investigate the structural dynamics and the stability of the complex. These findings suggested that the newly developed compounds represent promising preliminary hits for further optimization toward the treatment of diseases associated with Leishmania parasites.