Background Acute acquired comitant esotropia (AACE) can significantly impair binocular vision, and its prevalence is increasing. This study aims to compare the effectiveness of botulinum toxin (BTX) injections with strabismus surgery in patients diagnosed with AACE and to investigate the factors predicting success. Methods Sixty AACE patients were included in this prospective comparative clinical study. Twenty-seven patients underwent incisional strabismus surgery (surgery group) and 33 patients received BTX injection (chemodenervation group). Patients were followed up visit at 1, 3, and 6 months post-treatment. The primary outcome was the success rate at 6 months post-treatment, defined as a horizontal deviation of 10 prism diopters (PD) or less with confirmed binocular single vision. Secondary outcomes included risk factors for the recurrence of AACE. Results The present study included 27 patients in the surgery group and 33 in the chemodenervation group. No significant differences were observed in the motor success rate at 1 and 3 months post-treatment between the two groups. However, the surgery group had a significantly higher motor success rate compared to the chemodenervation group at 6 months post-treatment (100% vs. 69.7%, P < 0.001). The success rate of achieving stereopsis at near <= 100 arcsec in the chemodenervation group was significantly higher than in the surgery group at 1 month post-treatment (51.5% vs. 14.8%, P < 0.001). By the 6 months post-treatment, no significant differences were observed in sensory outcomes between the chemodenervation and surgery groups (P > 0.05 for all). In the chemodenervation group, patients with an anisometropia less than 1 dioptor (D)demonstrate significantly higher motor success rate, and better sensory outcomes, including stereopsis at near (84%, 21/25) and stereopsis at near <= 100 arcsec (56%, 14/25), compared to those with anisometropia of 1 D or more (P = 0.044). Conclusion The success rate after BTX injection was similar to that of surgery for 3 months but lower at 6 months post-treatment. Patients who received BTX showed restoration of stereopsis within the initial first postoperative month, with sustained preservation of this function across 6 months post-treatment. Anisometropia of 1 D may indicate suitability for BTX injection as a preferred treatment option for AACE. Trial registration This study was registered on the Chinese Clinical Trial Registry (ChiCTR2100053717. Registered 28 November 2021. https://www.chictr.org.cn/showprojEN.html?proj=140975).