The opioid epidemic has become a national health emergency in the USA. While heroin and prescription opioid abuse is not uncommon, synthetic opioid use has risen dramatically, creating a public safety concern. Like traditional opioids, novel synthetic opioids are abused due to their analgesic and euphoric effects. Some adverse side effects include respiratory distress, nausea and decreased consciousness. Synthetic opioids have emerged into the illicit and online drug market, including AH-7921, MT-45, U-series and W-series. Though originally developed by pharmaceutical companies, these substances are not well studied in humans and comprehensive analytical methods for detecting and quantifying these opioids are limited. Oral fluid is a useful biological matrix for determining recent drug use, does not require a trained medical professional, and can be collected under direct observation, deterring adulteration. The purpose of this research was to develop and validate a comprehensive analytical method for the detection and quantification of morphine, 6-acetylmorphine, buprenorphine, U-47700, U-49900, U-50488, AH-7921, MT-45, W-18 and W-15 in oral fluid collected via Quantisal. This was achieved by solid-phase extraction followed by liquid chromatography-tandem mass spectrometry. The limits of detection and quantitation were 5 ng/mL and 10 ng/mL, respectively. Linearity was observed between 10 and 500 ng/mL (R2 ≥ 0.9959). Bias and imprecision were <±11.1%. Matrix effects ranged from -21.1 to 13.7%. No carryover was detected following injection of the highest calibrator. All analytes were stable (within ±15% change from baseline) under all tested conditions (24 h at room temperature, 72 h at 4°C, and in the autosampler for 60 h at 4°C).