A simple method based on liquid chromatography-full-scan high-resolution accurate mass spectrometry (LC-HRMS) using a quadrupole time-of-flight (TOF) mass spectrometry was developed and optimized for corticosterone quantification in mouse plasma. Mouse plasma (100 μL) was extracted with methyl tert-butyl ether using prednisone as internal standard. Separation was performed on a short C18 column using a methanol-water gradient. Full-scan data were acquired in the TOF only mode, and extracted ion chromatograms were generated post-acquisition with the extract masses of the analytes. Enhanced sensitivity and reproducibility were acquired with optimized mass parameters. The calibration range was 8.24-412 ng/mL, and the limit of quantitation was 5.088 g/mL. Accuracy was between -5.9 and 8.6%. The precision of between-run (interday) and within-run (intraday) was within 5.6 and 6.9%, respectively. The LC-HRMS method was applied for plasma samples analysis from the stressed mice with and without ginseng treatment for the stress state estimation.