The current study was conducted to determine sulfonamides (SAs) and tetracyclines (TCs) residuals in farmed Nile Tilapia fish (Orechromis niloticus) using the solid phase extraction (SPE) technique and high performance liquid chromatography with diode array detection (HPLC-DAD). As well, to assess the potential health risk due to the consumption of contaminated fish following its household thermal processing. Tilapia samples were collected from four governorates in Egypt; El-Fayoum, Giza, Cairo, and Alexandria. The results showed that 56.3 % (27 out of 48 samples) of fish samples were free of antibiotics, while 10.4 % and 33.3 % of samples were contaminated by SAs and TCs, respectively. Besides, oxytetracycline (OTC) showed the highest detected concentrations ranged from 52.8 to 658.5 (μg/kg), followed by chlortetracycline (OTC) (35.89–109.76 μg/kg), and tetracycline (TC) (68.8–96.7 μg/kg). While the detected SAs were between 32.89 μg/kg (sulfamethazine: SMT) and 136.43 μg/kg (sulfadimethoxine: SDM). As well, sulfamethoxazole (SMX) showed an average concentration of 52.41 μg/kg. Notably, only 7 samples (out of 21 positive samples) had residual levels exceeded the permissible limits. The study also concluded that freezing fish at −18 °C for one week had no significant effect on the stability of SAs and TCs. As well, SAs showed more stability than TCs against the thermal processing for fish. Indeed, the stability of SAs and TCs antibiotics was arranged in a descending order, shown as follows: SMT > SDM > SMX > CTC > TC > OTC. Eventually, no potential risk to the Egyptian population was found from the consumption of the contaminated fish samples by SAs and TCs.