Occurrence of multi-class antibiotics in edible fish species from the Saudi market was investigated. A fast and sensitive UPLC-MS/MS method for simultaneous determination of selected fluoroquinolones, sulfonamides and macrolides in fish muscle was developed and validated. Sample clean up was performed using solid-phase extraction on Oasis HLB cartridges. The greenness profile of the developed method was evaluated using three assessment tools: analytical Eco-scale assessment method, green analytical procedure index and analytical greenness metric. Detection limits ranged from 0.008 to 0.35 μg/kg. The recovery ranged from 80.1 to 98.6% with RSDs ≤12.1%. The mean and maximum concentrations of the detected antibiotics in fish samples ranged between 0.28-19.15 and 3.50-112.00 µg/kg, respectively. Human antibiotics (clarithromycin and roxithromycin) were detected in 50% and 27.5% of the samples, respectively. The estimated daily intake for the detected antibiotics ranged from 0.10-6.61 ng/kg/ BW/day for Saudi adults. The health risk associated with fish consumption was evaluated. The results suggested that fish consumption may not pose a serious risk to consumers in Saudi Arabia. The developed method was fast, sensitive, cost-effective and environmentally friendly.