Dual-frequency ultrasound has been widely employed to enhance and regulate acoustic droplet vaporization (ADV) but the role of ultrasonic nonlinear effects on it remains unclear. The main objective of this study is to investigate the influence of nonlinear effects on the control of ADV nucleation under different dual-frequency focused ultrasound conditions. ADV nucleation of PFC nanodroplets activated by nonlinear dual-frequency ultrasound was modeled and parametric studies were conducted to investigate the influence of dual-frequency ultrasound frequency and acoustic power on the degree of nonlinearity (DoN), nucleation rates and dimensions of the nucleation region in a wide parameter range. The results showed that the ultrasonic nonlinearity caused a significant decrease in peak negative pressure due to waveform distortion, which leads to a lower nucleation rate in the nonlinear model compared to that in the linear model. Furthermore, the distributions of nucleation regions were also affected by the interaction between waves of different frequencies and cloud-like spatial distributions were produced, which could be modulated by the dual-frequency ultrasound parameters and have great potentials in the spatial regulation of the ADV and customized treatment protocols in clinical applications. In addition, represented by 1.5 MHz + 3 MHz, such a dual-frequency combination of fundamental and second harmonic could effectively enhance ultrasonic nonlinear effects with relatively lower peak negative pressure and higher DoN. Therefore, nonlinear effect of the dual-frequency ultrasound plays an important role in the ADV regulation, which should be considered in the numerical model and practical applications.