Purpose: Free flap reconstruction for lower extremity (LE) trauma has a higher failure rate than free flaps in other anatomic regions. Post-operative anticoagulation and antiplatelet therapy may influence LE free flap outcomes, but an optimal regimen has not been established. This study aims to evaluate complication rates associated with different anticoagulation and antiplatelet protocols in LE free flap reconstruction. Methods: Adult patients (≥18 years of age) with LE trauma requiring free flap reconstruction at our level 1 trauma center from 2016-2021 were included for retrospective chart review. Complications requiring reoperation were grouped into a composite variable named major complications (i.e. hematoma, flap thrombosis, flap necrosis >10%, infection requiring reoperation). Non-randomized patients were categorized into three groups based on postoperative anticoagulation or antiplatelet regimen (aspirin only, heparin only, and aspirin + heparin), with heparin being a subtherapeutic fixed-dose heparin infusion at 500-800 units/hour. Complication rates were compared across groups, and both univariate and multivariate analyses were conducted to identify associations with major complications. P-values were set at p < 0.05. Results: Of 191 patients, 37 (19.4%) received aspirin only, 76 (39.8%) received heparin only, and 78 (40.8%) received aspirin + heparin. Demographics were similar between the groups. On univariate analysis, the heparin group had a significantly lower rate of major complications (5.26%) compared to aspirin only (18.92%) and aspirin + heparin (20.51%) (p = 0.016); however, on multivariate analysis, when accounting for additional perioperative factors, no association between anticoagulation group and major complications was found. Conclusions: Our study found that neither aspirin alone, heparin alone, or aspirin + heparin demonstrated a more favorable association with LE free flap outcomes. To reduce bias from the study’s retrospective design and the surgeon’s discretion in choosing anticoagulation protocols, future research should randomize patients to standardized postoperative regimens to assess differences in complications.