Simple, reliable, sensitive, and accurate spectrofluorimetric and spectrophotometric methods were proposed for the determination of two selected analgesic drugs, namely tramadol and morphine, in pharmaceuticals and biological fluids. The proposed methods were based on the oxidation of the studied drugs by Cerium (Ce)IV in an acidic medium. The spectrofluorimetric method is based on measuring the relative fluorescence intensity of Ce(III) arising from Ce(IV) at 350 nm with an excitation wavelength at 250 nm. The spectrophotometric method involves on addition of a known excess of Ce(IV) to the studied drugs in an acid medium, followed by the determination of residual Ce(IV) by reacting with a fixed amount of methyl orange and measuring the absorbance at 510 nm. Different variables affecting the reaction conditions, such as the concentrations of Ce(IV), type and concentration of the acid medium, reaction time, temperature, and the diluting solvents, were carefully studied and optimized.