To establish HPLC-MS/MS method for simultaneous determination of 14 toxic or active components in Fuzi formula granules, and further analyze the quality consistency of 29 batches of formula granules by considering the cluster analysis (CA), principal component analysis (PCA), and partial least squares discriminant analysis (PLS-DA) and other chemometrics methods. Phenomenonex Gemini C18 column (4.6 mm×150 mm, 5 μm) was used with 0.1% formic acid solution (A) -acetonitrile (B) as the mobile phase. The mass spectrum was scanned by ESI⁺ multiple reaction monitoring (MRM) mode. The contents of aconitine, mesaconitine, hypaconitine, Indaconitine, benzoylaconine, benzoylmesaconine, benzoylhypaconitine, aconine, fuziline, neoline, talatisamine, songorine, higenamine and salsoline were determined. The results showed that 14 compounds had a good linear relationship within their respective concentration range (R²>0.990 0). The limit of quantification was 2.07-7.71 mg·L⁻¹, and the average recovery was 96.07%-102.2%. The content determination results demonstrated that all batches of Fuzi formula granules had very low hypertoxic ingredients and high safety, while the content of active ingredients was greatly different. CA and PCA results showed that there were significant differences in the formula granules between two manufacturers; even though the different batches of samples from the same manufacturer had certain differences, but the difference in manufacturer A was less than that of B. Further PLS-DA showed that the content of cardiotonic substance salsola in the formula granules from manufacturer A was generally higher, while the contents of analgesic and anti-inflammatory substances benzoylmesaconitine and fuziline were generally lower than those in the products from manufacturer B. In conclusion, the safety of Fuzi formula granules was assured well, but the consistency needed to be improved. We recommend that all manufacturers establish strict standard for decoctions in the production process, and form a unified standard method to produce better Fuzi formula granules.