Leishmaniasis and toxoplasmosis are neglected parasitic diseases that remain major global health concerns due to limited therapeutic options, drug toxicity, and emerging resistance. In this context, the development of new antiparasitic agents based on natural product scaffolds is highly relevant. Totarol, a naturally occurring abietane-type diterpene isolated from Tetraclinis articulata, was used as a starting scaffold for hemisynthetic modification. A series of totarol-derived functionalized ketones, including α-bromoketone (4) and chalcone derivatives (5a–g), was synthesized and fully characterized by NMR, IR, and HRMS analyses. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania major and Toxoplasma gondii. Compound 4 showed the highest activity, with half-maximal inhibitory concentration (IC₅₀) values of 3.2–5.3 µM against Leishmania major and 6.1 µM against T. gondii. However, compound 4 showed none strong host–cell selectivity, with selectivity indices of 0.79–1.5. Docking against L. major pteridine reductase 1 (PTR1) gave a Glide XP score of −5.3 kcal/mol, and the modeled complex persisted during a 100 ns molecular dynamics simulation. These computational results generate a hypothesis for antileishmanial activity without demonstrating PTR1 inhibition or explaining T. gondii activity. The active structures require substantial optimization of selectivity before consideration as antiparasitic candidates.