A novel method was developed for simultaneous determination of 10 progestin residues in fish by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS) combined with a modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) method. The homogenized samples were dispersed by water, extracted with acetonitrile, and then purified by QuEChERS reagent. The concentrated analytes were detected by UPLC-Q-TOF/MS. High linearities (  > 0.995) and recoveries (85.71-117.08%) at three spiked levels (5, 10, and 20 ng/g) and low relative standard deviation values (<8.83%,  = 7) and limits of detection (0.23-0.66 ng/g) were obtained. This method is simple, rapid, reliable, sensitive, and efficient and can be used for monitoring of progestin residues in fish. This method provides a strong guarantee to deal with food emergencies for the laboratory, provides technical support for the screening and quantitative detection of progesterone in fish, and provides technical support for the food safety of aquatic products.