We extended our previous work to synthesize a series of 5-(3-substituted-1-adamantyl)-2-imidazolines (4a–s) with hydrophobic substituents (cyclopentyl, cyclohexyl, phenyl, etc.) at the C3 position of the adamantane skeleton. The compounds were prepared by condensing 1-(1-adamantyl)ethylenediamines with formamidine acetate/acetamidine hydrochloride or reacting with cyanogen bromide. Anti-Trypanosoma brucei activity screening revealed that introducing cyclopentyl or cyclohexyl groups at C3 of adamantane enhanced trypanocidal activity compared to unsubstituted analogues 2, while phenyl substitution at C3 of adamantane or N1 of imidazoline drastically reduced activity. Cyclopentyl or cyclohexyl substituted derivatives showed similar activity, with compound 4q (bearing cyclopentyl at C3 of adamantane and cyclohexyl at N1 of imidazoline) being the most active (IC50 = 0.65 μM). Additionally, introducing an amino group at C2 of the imidazoline ring significantly reduced cytotoxicity for some derivatives (e.g., 4e, 4f, 4h). Conclusion: Cyclopentyl or cyclohexyl lipophilic substituents in the 5-(1-adamantyl)-2-imidazoline scaffold improve efficacy against bloodstream forms of African trypanosomes, though their precise targets in T. brucei remain to be determined.