Background: Several malreduction criteria have been proposed for ankle surgery, but the criteria of most importance for functional outcome remain undetermined. Furthermore, the acute inflammatory response in the ankle joint after fracture is hypothesized to result in osteoarthritis development, but no study has investigated the correlation between the levels of these inflammatory cytokines and post-surgical functional outcomes. We aimed to identify malreduction criteria and inflammatory cytokines associated with functional outcome after ankle surgery. Methods: During surgery, synovial fluid from the fractured and healthy contralateral ankles of 46 patients was collected for chemiluminescence analysis of 22 inflammatory cytokines and metabolic proteins. The quality of fracture reduction was based on 9 criteria on plain X-rays and 5 criteria on weight-bearing computed tomography (WBCT) scans. After 3 and 12 months, we recorded scores on American Orthopedic Foot and Ankle Society (AOFAS) scale, the Danish version of Foot Function Index (FFI-DK), EQ-5D-5L index score, the Kellgren-Lawrence score, and joint space narrowing. Results: Tibiofibular (TF) overlap (p = 0.02) and dime sign (p = 0.008) correlated with FFI-DK. Tibiotalar tilt correlated positively with joint space narrowing at 3 months (p = 0.01) and 12 months (p = 0.03). TF widening correlated with FFI-DK (p = 0.04), AOFAS (p = 0.02), and EQ-5D-5L (p = 0.02). No consistent correlations between synovial cytokine levels and functional outcomes were found at 12 months. Conclusions: Malreduction of TF overlap, TF widening, and tibiotalar tilt were the most important criteria for functional outcome after ankle surgery. Increased inflammatory cytokine levels after fracture did not affect functional outcome at 12 months. Trial registration: This cohort study is registered the 10th of December 2018 at ClinicalTrials.gov (NCT03769909), was approved by the local committee on health ethics (The Regional Committees on Health Research Ethics for Southern Denmark: J.No. S-20170139), and was reported to the National Danish Data Protection Agency (17/28505).