Efonidipine hydrochloride is a new generation dihydropyridine calcium channel blocker designed to inhibit both T-type and L-type calcium channels. For the first time, a simple and robust LC–MS/MS method was developed for the determination of efonidipine in human plasma over the range of 0.100–20.0 ng/mL. Efonidipine was extracted from plasma by an LLE procedure, separated by LC and detected by MS/MS in positive mode ESI. The method was validated for selectivity, carryover, sensitivity, extraction recovery, matrix effects, linearity, accuracy and precision, dilution integrity and stability studies. The calibration curves were linear over 0.100–20.0 ng/mL (r ≥ 0.9980). The lower limit of quantification (LLOQ) was established at 0.100 ng/mL. Intra- and inter-day precisions (LLOQ, low-QC, mid-QC, high-QC and ultra-high QC) were less than 12.5% in terms of relative standard deviation (RSD), and accuracies were between −5.0% and 5.0% in terms of relative error (RE). Matrix effect was acceptable (105.6–110.2%) and extraction recovery was reproducible (85.8–91.3%, RSD ≤ 10.0%). Efonidipine was stable in the investigated conditions. The method was applied to the pharmacokinetics of efonidipine in human subject.