Several validated methods exist for the quantitation of antibiotics in seafood with ultra-high pressure liquid chromatography coupled with tandem spectrometry (UPLC-MS/MS). To our knowledge, none have explored the effects of co-eluting matrix components on the accuracy of quantitation. Such matrix effects could disproportionally change the ionization of analytes and their respective surrogate/internal standards during UPLC-MS/MS analysis, resulting in over- or under-estimation of antibiotic values. In this study, we measured matrix effects, alongside extraction recoveries for 30 antibiotics and their respective class-specific surrogate standards in Sockeye, King and Ivory (non-pigmented) salmon extracted using the QUEChERS method. A modified QUEChERS method involving dispersive or hydrophilic-lipophilic balance (HLB) solid phase extraction (SPE) was also tested on Sockeye salmon. Despite acceptable extraction recoveries for most antibiotics extracted using the QUEChERS method, significant matrix effects were observed for most antibiotic standards. Dispersive or HLB SPE clean-up did not improve analyte recoveries from Sockeye salmon, and in some cases, increased matrix effects. Accuracy and sensitivity were reduced when matrix effects were high. Our results demonstrate that matrix components in salmon cause matrix effects on antibiotics during UPLC-MS/MS analysis which could impact the accuracy and sensitivity of the analysis.