The FDA authorized Encorafenib on April 8, 2020, taken along with cetuximab to treat patients (adults) with advanced metastatic colo-rectal cancers, who have a mutation of BRAF-V600E and have previously undergone therapy. No documented techniques for the simultaneous quantitation of Encorafenib and Cetuximab using LC-MS/MS was available, so a reliable, fast, and unique method was developed and validated. Method development involved optimizing chromatographic and mass spectrometric conditions to achieve high sensitivity and specificity. The method was validated per FDA guidelines, evaluating parameters such as linearity, precision, accuracy, recovery, and stability under various conditions. Mass ion pairs were tracked using multiple reaction monitoring (MRM) in positive polarity mode and the precursor to daughter ion transition m/z values for Encorafenib, Cetuximab(peptide), and Tofacitinib (internal reference) are 540.15 → 369.85, 643.34 → 653.31, and 313.17 → 221.05, respectively. The calibration curves demonstrated excellent linearity over 3.75-150 ng/mL ranges for Encorafenib and 0.25-10 ng/mL for Cetuximab. The MS