In this study, design of experiments (DoE) was employed to develop a single injection method using a headspace gas chromatograph with flame ionization detector for resolution of residual solvents of United States Pharmacopeia (USP) listed classes 1 and 2, against current recommendation of independent injections. G43 column (6% cyanopropylphenyl and 94% dimethylpolysiloxane) and nitrogen were used as the stationary phase and carrier gas, respectively. Initial temperature, hold time, temperature ramp and carrier gas velocity were the critical method parameters. Resolution of 1,1,1-trichloroethane and tetrahydrofuan (THF); THF and chloroform; benzene and 1,2-dichloroethane (DCE), and 1,2-dimethoxyethane and DCE were selected as critical quality attributes. These were optimized by DoE that resulted in resolution of >1.34 among various solvents. The separation of all the solvents was achieved within total run time of 77 min. A better resolution of 2.66 was observed in the case of acetonitrile and methylene chloride; there was improved Signal/Noise ratio of 8.86 for 1,1,1-trichloroethane; tailing factor for pyridine was 1.00, and the method showed acceptable repeatability of peak areas (%RSDmax = 11.53) and retention times (%RSDmax = 0.45). Thus, while system suitability criteria and validation results very well met the USP requirements, the optimized method proposed in this study proved advantageous additionally in terms of single injection; short run time, and use of nitrogen as a carrier gas instead of costly helium in the USP method.