A selective, sensitive, precise and accurate liquid chromatography-tandem mass spectrometry method was developed and validated for the concurrent determination of antidiabetic drugs, empagliflozin and linagliptin in human plasma. Sample preparation was tested on several reversed-phase solid-phase extraction (SPE) sorbents with different chemistries like hydrophilic-lipophilic balance (Oasis HLB), mixed-mode cation exchange (Oasis MCX) and weak-cation exchange (Oasis WCX). SPE conditions like sample pH, washing and elution solvents were suitably optimized. Best results were obtained using Oasis MCX cartridges in terms of extraction recovery (78–88%) and matrix effects (~3.0%) for both the analytes. Chromatographic conditions for the separation of analytes and their labeled internal standards (ISs) were established on XSelect HSS Cyano (50 × 2.1 mm, 3.5 μm) column using 2 mM ammonium acetate buffer and acetonitrile as the mobile phase. Detection of analytes was achieved using electrospray ionization in the positive mode. For quantitative analysis, multiple reaction monitoring transitions were m/z 451.3 → 71.1 for empagliflozin and m/z 473.2 → 420.2 for linagliptin. Standard curve concentrations were validated in the range of 1.50–1500 ng/mL for empagliflozin and 0.015–15.0 ng/mL for linagliptin. The intra-batch and inter-batch precision (% CV) was <3.7 for both the drugs. The stability of the analytes established under different storage conditions was found to be appropriate for routine laboratory practices. The validated method was used to study the pharmacokinetics of the drugs using a single oral dose of fixed-dose combination tablet consisting of 25 mg empagliflozin and 5 mg linagliptin in healthy subjects.