Nickel oxide nanoparticles (NiO NPs) as a new catalyst were fabricated via the sol-gel method. The characterization of the synthesized nanocatalyst was assessed by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Xray diffraction (XRD), and Fourier-transform infrared (FT-IR) spectroscopy. Its catalytic efficiency was evaluated in the aldol condensation reaction using an environmentally-friendly procedure. Among various solvents, including dimethyl sulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (CH 2 Cl 2 ), and water, the highest yield (82 %) was related to the water with room temperature, the reaction time of 5 h, and amount catalyst of 30 mmol. Response surface methodology (RSM) based on the central composite design (CCD) was applied to optimize the experimental factors of aldol reaction, as well as the investigation of interaction between the parameters. The results revealed that the temperature of 25 °C and a catalyst amount of 30 mmol had high performance (73.93 %). The preparation of catalyst was accomplished using inexpensive and easily available materials. The synthesized NPs were found to be an efficient and reusable catalyst for the aldol reaction.