The present study aimed to investigate the serum levels of caspase-1 in patients with high-energy pilon fractures, and its correlation with prognosis and clinical results. In this prospective study, 136 patients with high-energy pilon fractures who were treated with a locking plate combined with ankle arthroscopy from July 2015 to July 2020 were included. The treatment efficacy was evaluated according to the Mazur ankle function score. Serum caspase-1, interleukin (IL)-6, IL-1β and C-reactive protein (CRP) levels were measured using enzyme-linked immunosorbent assay. Reverse transcription-quantitative PCR was used to measure the mRNA expression of caspase-1. Additionally, demographic data and clinical characteristics, such as sex, age, intraoperative blood loss, fracture healing time, fracture classification and complications were collected and analyzed. The study revealed that the intraoperative blood loss, proportion of Ruedi-Allgower III and the serum levels of caspase-1 in the poor prognosis group were significantly higher compared with those in the good prognosis group. Additionally, patients with high-energy pilon fractures in the poor prognosis group exhibited significantly higher levels of caspase-1 and IL-1β serum levels at all time points in contrast to those in the good prognosis group. Spearman's analysis revealed a significant association between caspase-1, IL-1β levels and Mazur scores. Furthermore, caspase-1 could serve as a potential diagnostic biomarker for poor prognosis of patients with high-energy pilon fractures. Caspase-1, IL-1β, intraoperative blood loss and Ruedi-Allgower grade were the risk factors for poor prognosis in patients with high-energy pilon fractures. In summary, this study demonstrated that serum caspase-1 levels were progressively reduced during the treatment of high-energy pilon fractures patients and prominently lowered in those with a favorable prognosis. These findings could provide novel targets and a comprehensive approach to protecting patients with high-energy pilon fractures.