Objective To explore the differential diagnostic indicators of adult-onset Still's disease (AOSD) from other fever of unknown origin (FUO). Methods The clinical data and laboratory indicators of 177 AOSD patients and 163 FUO patients who were hospitalized in the First Affiliated Hospital of Army Medical University from January 2010 to May 2021 were collected, and the patients were randomly divided into training group and verification group. Statistically significant variables were extracted from univariate analysis for receiver operating characteristic (ROC) curve analysis and the best cut-off value of the variables was obtained. The differential diagnostic indicators were extracted by multivariate logistic regression analysis and nomogram model was constructed. ROC curve, calibration curve, and decision curve analysis were used to evaluate the accuracy and stability of nomogram. Results Univariate analysis revealed that there were significant differences in 4 clinical features (arthralgia, rash, pharyngeal pain, myalgia) and 14 laboratory parameters [white blood cell count (WBC), monocyte percentage, neutrophil percentage, lymphocyte percentage, platelet count, C-reactive protein, interleukin-6 (IL-6), ferritin, globulin, immunoglobulin A, and immunoglobulin G (IgG), creatine kinase, creatinine and complement C3]. Multivariate analysis suggested that arthralgia, WBC ≥9.995×10⁹/L, IL-6 ≥98.13 ng/L, ferritin ≥507.37 ng/ml, globulin ≤36.58g/L, IgG ≤13.59g/L, complement C3 ≥1.27 g/L were related with AOSD. The area under curve (AUC) values of training group and verification group were 0.917 (95%CI 0.883-0.951) and 0.869 (95%CI 0.802-0.936), respectively. The calibration curves showed good consistency. The decision curve analysis showed that training group and verification group had a large positive rate of return in the wide risk range of 5%-85% and 10%-85%, respectively. Conclusions This study has established a relatively accurate AOSD differential diagnosis model. The combination of arthralgia, WBC, IL-6, ferritin, globulin, IgG and complement C3 may help to distinguish AOSD from other causes of FUO.