Although formononetin has a considerable biological activity, its therapeutic use is limited by its low solubility. Formononetin was dissolved in ethanol, methanol, N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) in this investigation, the antisolvent precipitation procedure with the assistance of an external ultrasonic probe was used to manufacture the formononetin nano-particles. The ideal parameters for response surface BBD optimization are as follows: feed volume flow rate of 6 mL/min; ultrasonic power of 860 W; and liquid-liquid ratio of 1:12.5. The formononetin nano-particles have a smaller particle diameter than raw sample; the lowest size can be as small as (329 ± 1.99) nm, which is 45 times smaller than raw. An in vitro digestion test using a solution that simulated intestinal solution revealed that the release rate of the nano-particle was 1.75 times than that of the raw formononetin. The formononetin nano-particles generated by the aforementioned four solvents have the following order of diameter: ethanol > methanol > DMF > DMSO. This study provided a technical reference for the functional food components in deep processing.