Fish such as tilapia (Oreochromis niloticus) and catfish (Clarias gariepinus) is an important source of high biological value animal protein. Fish can be exposed to antimicrobials in intensive aquaculture systems or exposed to remnants of the antimicrobials released to various water bodies via drainage systems. This study aimed at screening for antimicrobial residues in two major fish species commonly consumed in Egypt, namely, tilapia, and catfish, either in wild or cultured fish using a microbial inhibition assay. Besides, quantitative estimation of tetracycline (oxytetracycline and doxycycline) residues in the edible fish muscles was carried out using the solid phase extraction (SPE) technique and high-performance liquid chromatography with photodiode-array detection (HPLC-PAD). In addition, the effects of different cooking methods (pan-frying, grilling, and microwaving) on oxytetracycline and doxycycline residues in tilapia and catfish were investigated. The microbiological inhibition assay revealed that 2, 24, 18, and 32% of the examined wild tilapia, cultured tilapia, wild catfish, and cultured catfish, respectively, contained antibiotic residues. Cultured tilapia, wild catfish, and cultured catfish had mean concentrations of oxytetracycline residues of 0.147 ± 0.067, 0.106 ± 0.046, and 0.313 ± 0.044 µg/g. 3 (6%), 4 (8%), and 9 (18%) of the sampled cultured tilapia, wild catfish, and cultured catfish exceeded the established maximum permissible limits (MPL) of tetracycline (0.100 ng/g). The mean concentrations of doxycycline residues were 0.276 ± 0.045, 0.026 ± 0.004, and 0.070 ± 0.010 µg/g in cultured tilapia, wild catfish, and cultured catfish, respectively, with 2 (4%) of the cultured tilapia exceeding the MPL of doxycycline. Consumption of fish with high residual levels of tetracyclines might pose potential health risks to consumers. In an experimental trial, heat treatment of tilapia and catfish could significantly reduce both oxytetracycline and doxycycline residues, particularly grilling had the highest reduction rates.