Objective To evaluate the effectiveness of lymphaticovenular anastomosis (LVA) combined with perioperative targeted multi-layer circular lymphatic drainage in the treatment of secondary lower limb lymphedema using a prospective randomized controlled trial. Methods In a prospective randomized controlled trial, 80 patients with secondary lower limb lymphedema admitted between January 2023 and September 2025 were initially enrolled and allocated to either the trial group (LVA+targeted lymphatic drainage) or the control group (LVA+conventional lymphatic drainage), 40 in each group. After 2 dropouts in the control group, 78 patients (40 in the trial group, 38 in the control group) were included for analysis. There was no significant difference in the baseline data (P>0.05), such as age, gender, disease duration, and preoperative lower limb circumference difference, functional scores, and levels of vascular endothelial growth factor C (VEGF-C), transforming growth factor β1 (TGF-β1), and interleukin 6 (IL-6). Both groups underwent LVA. The trial group received perioperative targeted multi-layer circular lymphatic drainage, while the control group received conventional manual lymphatic drainage. Changes in lower limb circumference difference, functional scores, and levels of VEGF-C, TGF-β1, and IL-6 were compared between the two groups at various time points before and after operation. Overall effectiveness and safety were also assessed. Results All patients were followed up 3-12 months (mean, 6.5 months). Postoperatively, the trial group demonstrated significantly better functional recovery and a superior trend in lower limb circumference reduction at all time points compared to the control group (P<0.05). Serological analysis indicated a more pronounced increase in VEGF-C level in the trial group (P<0.05), and a downward trend in TGF-β1 and IL-6 levels in both groups (P<0.05); no significant difference was observed in TGF-β1 and IL-6 levels between groups (P>0.05). At 3 months after operation, indocyanine green fluorescence (ICG) lymphography showed an anastomosis patency rate of 95.0% (38/40) in the trial group, significantly higher than the 68.4% (26/38) in the control group (P<0.05). The overall effectiveness was rated as significantly effective in 30 cases and effective in 15 cases in the trial group, while as significantly effective in 15 cases, effective in 15 cases, and ineffective in 8 cases in the control group. The difference between groups was significant (P<0.05). The incidence of complications showed no significant difference between trial group and control group (2.5% vs 7.9%, P>0.05). ConclusionThe application of targeted multi-layer circular lymphatic drainage during the perioperative period of LVA is safe and effective. It significantly promotes lower limb circumference reduction and functional recovery without increasing the risk of complications.