A novel sol-gel method was implied to prepare CuO-doped ZnO nanoparticles. XRD and SEM techniques were used to characterize the CuO-doped ZnO sample. The photocatalytic degradation of Lidocaine HCl was investigated by two methods. The degradation was studied under different conditions such as the amount of photocatalyst, pH of the system, initial concentration, presence of electron acceptor, and presence of anions. The results showed that they strongly affected the photocatalytic degradation of Lidocaine HCl. The photodegradation efficiency of drug increased with the increase of the irradiation time. After 6 h irradiation with 400-W mercury lamp, about 93% removal of Lidocaine HCl was achieved. The degree of photodegradation obtained by Taguchi method compatible with the trial-and-error method showed reliable results.