An improved LC–MS/MS method was developed and validated for lercanidipine determination in human plasma using solid-phase extraction with lercanidipine-d3 as an internal standard. Pharmacokinetic parameters (Cmax, AUC, Tmax, T1/2, Kel) were assessed in bioequivalence studies. Method validation showed high accuracy, reproducibility, and no in vivo enantiomer conversion. The R-enantiomer protects S-lercanidipine from first-pass metabolism. The study confirms the method's reliability for pharmacokinetic and bioequivalence analysis of lercanidipine.