This article describes the development and validation of a liquid-chromatography coupled with tandem mass spectrometry (LC-MS/MS) assay for the simultaneous quantitation of the BRAF inhibitors dabrafenib and encorafenib, and semi-quantitation of their major metabolites (i.e., carboxy-dabrafenib, desmethyl-dabrafenib, hydroxy-dabrafenib, M42.5A) in human plasma. Analytes were extracted from human plasma by protein precipitation, followed by reversed phase high-performance liquid chromatography. Analyte detection was performed using tandem mass spectrometry with heated electrospray ionization operating in positive ion mode. The assay was validated in accordance with the current U.S. Food and Drug Administration Guidance on Bioanalytical Method Validation. Results showed that measurements were both accurate (94.6-112.0 %) and precise (within-run: 1.9-3.4 %; between-run: 1.7-12.0 %) spanning a concentration range of 5 to 2000 ng/mL for dabrafenib and 10 to 4000 ng/mL for encorafenib. Recoveries for these analytes were consistent with mean values ranging from 85.6 % to 90.9 %. The mean internal standard-normalized matrix factors for each drug ranged between 0.87 and 0.98 and were found to be precise (% RSD <6.4 %). Dabrafenib and encorafenib were stable in the final extract and in human plasma held under various storage conditions. The metabolites also passed the validation criteria for precision and selectivity. Finally, the clinical applicability of the assay was confirmed by (semi-)quantitation of all six analytes in plasma samples from cancer patients receiving standard-of-care treatment with dabrafenib and encorafenib. Reproducibility of the measured analyte concentrations in study samples was confirmed successfully by incurred sample reanalysis. In conclusion, this sensitive LC-MS/MS assay has been validated successfully and is suitable for therapeutic drug monitoring of dabrafenib and encorafenib and clinical pharmacokinetic studies with these BRAF inhibitors.