The cytological diagnosis of atypical squamous cells that cannot exclude high-grade squamous intraepithelial lesions (ASC-H) is subjective and entails great variation in the risk of HSIL+. Therefore, we retrospectively analyzed the clinicopathological outcomes of patients with ASC-H cytology from January 2018 to June 2021 to determine associated predictors for diagnosing HSIL+ and explore their appropriate clinical management. Overall, 279 patients with ASC-H cytology were enrolled, 64.9% (181/279) of whom were histopathologically confirmed as HSIL+. Further analysis showed that only human papillomavirus (HPV) positivity was an independent risk factor for HSIL+ in ASC-H patients. Additionally, no significant difference was observed in the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the three HPV testing methods (hybrid capture (HC) II, HPV E6E7 mRNA and HPV genotyping testing) for detecting HSIL+ (p > 0.05). The perfect agreement between colposcopy and final histology was 40.5%, with a κ value of 0.145. The sensitivity, specificity, PPV and NPV of colposcopy for detecting HSIL+ were 32.6%, 91.8%, 87.9% and 42.3%, respectively. After cervical conization, none of the patients diagnosed with normal/benign histopathology by cervical biopsy was reclassified to HSIL+, while 39.5% (17/43) of the low-grade squamous intraepithelial lesion (LSIL) patients were reclassified as HSIL. During follow-up, ASC-H patients diagnosed with LSIL had a high rate of normalization (70%) and a low rates of persistence (20%) and progression (10%). In four ASC-H patients younger than 30 years old with HSIL (cervical intraepithelial neoplasia (CIN) 2), two normalized and two persisted during follow-up. In conclusion, ASC-H patients should be directly referred for colposcopy and undergo biopsy irrespective of their age, menopausal status and HPV status. Relatively conservative management might be more suitable for ASC-H patients with LSIL− or ASC-H patients younger than 30 years with HSIL (CIN2).