The increase in the consumption of antidepressants is a public health problem worldwide, as these are a class of compounds widely used in the treatment of several illnesses, such as depression and anxiety. This work aimed to develop and optimize a method for the quantification of a number of antidepressants and their metabolites (fluoxetine, venlafaxine, O-desmethylvenlafaxine, citalopram, sertraline, and paroxetine) in 100 µL of oral fluid using the dried saliva spots (DSS) sampling approach and gas chromatography coupled with tandem mass spectrometry (GC–MS/MS). The method was validated, presenting linearity within the studied range, with detection and quantification limits ranging between 10 and 100 ng/mL, and coefficients of determination (R2) of at least 0.99 for all analytes. Recoveries were between approximately 13 and 46%. The analysis of precision and accuracy presented acceptable coefficients of variation and relative errors, considering the criteria usually accepted in the validation of bioanalytical procedures. The method herein described is the first to be reported using DSS for the extraction of antidepressants, proving to be a sensitive, simple, and fast alternative to conventional techniques, and capable of being routinely applied in clinical and forensic toxicology scenarios.