The term “antivirals” has been associated with COVID-19 during the period when the usage of this specific class of medications has increased. Nirmatrelvir, a protease inhibitor, is used to treat mild to moderate COVID-19 symptoms by stopping SARS-COV-2 reproduction. With deucravacitinib serving as the internal standard, liquid chromatography-tandem mass spectroscopy in human plasma was used to provide a quick, simple, innovative, trustworthy, and sensitive approach. Liquid-liquid extraction was used to separate nirmatrelvir and the internal standard. The extracted sample was then run through a chromatographic system with ACE-C18 column (4.6 × 100 mm, 5 μm); and mobile phase with methanol and 2 mM ammonium formate in a ratio of 80:20, and a flow rate of 1.00 mL/min. The system operates for three minutes in multiple reaction monitoring mode at the ABSCIEX API 4000 mass spectrometer using electron spray ionization. Nirmatrelvir ion transitions are 500.10 to 110.10, while deucravacitinib are 426.30 to 358.20. The validation was conducted using a concentration range of 5.00 to 4000 ng/mL, and the results showed that the selectivity, accuracy, precision, linearity, and selectivity were all within the acceptability limits.