A nano-active fluid was prepared using positively charged calcium carbonate nanoparticles and cationic-nonionic gemini surfactants as raw materials. The mechanism of synergistic modification of surface wettability of oil-wet sandstone by calcium carbonate nanoparticles and cationic-nonionic gemini surfactants in a novel nano-active fluid was investigated by zeta potential, infrared (IR), quartz crystal microbalance (QCM), contact angle measurements and spontaneous imbibition experiments in this paper. The results showed that the intensity of carbonyl absorption peak of infrared spectrum for the surface of sandstone treated with the novel nano-active fluid was lower than that treated with the gemini surfactant. When the mass fraction of cationic-nonionic gemini surfactants was high (>0.003 %), the formation and desorption of the ion pairs produced by the cationic-nonionic gemini surfactants and carboxyl groups of crude oil are promoted by the calcium carbonate particles in the nano-active fluid, resulting in a higher reduction of the Δf (the amount of resonance frequency change) for the sandstone surface treated by the nano-active fluid than that for the cationic-nonionic gemini surfactant. The fact that the novel nano-active fluids are more effective than the single gemini surfactants and calcium carbonate nanoparticles in altering the wettability of oil-wet sandstone surfaces is confirmed by the contact angle measurements. The two components in the nano-active fluid act synergistically.