A new smart spectrofluorometric method was developed for the quantitation of amoxicillin and ethopabate simultaneously for the first time. The method is based on measuring their first derivative synchronous amplitudes in water at Δλ = 80 nm. The peak amplitudes were recorded at their crossing points; 240 nm for amoxicillin and 280 nm for ethopabate. The method is linear over the concentration ranges of 100.0-1,000.0 ng/ml for amoxicillin and 2.0-20.0 ng/ml for ethopabate. The limits of detection were 20.0 ng/ml and 0.58 ng/ml and limits of quantitation were 60.0 ng/ml and 1.92 ng/ml for amoxicillin and ethopabate, respectively. The method sensitivity permitted the determination of the two drugs below their maximum residue limit stated by the federal regulations. The developed method was applicable to the analysis of both drugs in the veterinary powders, feed premix, chicken tissues, liver, kidney, and eggs samples with percentage recoveries ranging 93.72-104.71%.