The effect of ethanol or acetone, as oil phase solvents, upon the form of paeonol-loaded poly(butyl-2-cyanoacrylate) encapsulated nanocapsules (Pae@PNCs) by interfacial spontaneously polymerization were investigated. Pae@PNCs characterizations including morphology, radius distribution, polydispersity index (PDI), particle size, zeta potential, entrapment efficiency (EE%), drug loading (DL%) and in vitro paeonol release kinetics were evaluated. Results show that 100% acetone have a significant effect on forming nanocapsules, which showed the smaller size (168.3 ± 6.76 nm) under scanning electron microscopy (SEM) and one radius distribution by the particle size analyser. The data showed that using 100% acetone to prepare Pae@PNCs was leading to smaller particle size and lower polydispersity index (PDI), higher zeta potential, better EE (%) and perfect DL (%), which is linear decrease in radius (r = 0.939) and PDI (r = 0.974) and linear increase EE% (r = 0.9879) and DL% (r = 0.9892) with the acetone concentration (range 10-100% v/v). Paeonol encapsulated into and adhered on PNCs were confirmed by UV-Visible spectra (UV-Vis), Fourier transform infrared spectroscopy (FTIR) and Differential scanning calorimetry (DSC). Drug release behavior in vitro showed that 100% acetone as solvents on developing Pae@PNCs have greater advantages in controlling and prolonging paeonol release. Results demonstrated that solvents have a significant influence on forming Pae@PNCs.