Background and Objective <p>Chronic venous disease (CVD) substantially impacts patients’ quality of life (QoL) owing to leg symptoms such as pain, swelling, and discomfort. The aim of this meta-analysis was to evaluate the effects of micronized purified flavonoid fraction (MPFF) treatment on QoL in patients with CVD.</p> Methods <p>A systematic review conducted in December 2023 identified studies investigating the efficacy of oral MPFF treatment (1000 mg daily for at least 1 month) on QoL in patients with CVD. Eligible prospective studies included randomized controlled trials (RCTs) and non-RCTs (comparative, single-arm, and observational studies). Medline, Embase, and Cochrane databases were searched. Mean changes (MC) from baseline to the last postbaseline value in the global QoL score (0–100) were estimated using single-group random-effects meta-analysis. Secondary outcomes included all dimensions of QoL score (pain, physical, social, and psychological) and CVD symptom scores (using 10-cm visual analog scale [VAS]) and percentage of patients with complete resolution for heaviness and cramps. Risk of bias was assessed using the Cochrane tools.</p> Results <p>In total, 10 of 317 studies were retained for the analysis. These studies conducted worldwide included 5654 patients allocated to MPFF treatment; nearly all (99.6%) were treated for at least 2 months. Mean (standard deviation [SD]) age was 45.6 (6.7) years, with mostly females (81.3%) and overweight (body mass index [BMI] of 25.9 [3.5] kg/m²) patients. The distribution of Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) classes was: 37.3% (C2), 24.0% (C3), 21.2% (C1), 14.1% (C4), and 3.2% (C0s). Two studies had low risk of bias, four had some concerns, and four had high risk. There was no strong evidence of publication bias (Egger’s test <i>P</i> = 0.083).</p> <p>Patients’ global QoL score significantly improved post treatment: MC of − 17.1 (95% confidence interval (CI) [− 20.0, − 14.1], <i>I</i>² = 96.3%), with greater reductions observed over longer treatment durations, from − 13.0 (− 17.7, − 8.3) for 1–2 months to − 20.0 (− 24.6, − 15.5) for 6 months treatment (all <i>P</i> &lt; 0.001). Sensitivity analysis excluding studies with a high risk of bias showed consistent results with the main analysis. Subgroup analysis between RCTs and non-RCTs showed comparable reductions across both study designs.</p> <p>QoL dimensions showed improvements in pain, physical function, psychological well-being, and social engagement (all <i>P</i> &lt; 0.001). MPFF treatment also significantly alleviated CVD symptoms such as pain, heaviness, and discomfort, with improvements demonstrated by VAS scores (all <i>P</i> &lt; 0.001). A significant percentage of patients reported complete resolution of heaviness (78.7%) and cramps (95.3%), both <i>P</i> &lt; 0.001. Heterogeneity was high across studies (<i>I</i>² &gt; 80% in most analyses).</p> Conclusions <p>This meta-analysis showed that MPFF treatment was associated with improvements in QoL globally and across all dimensions for patients with CVD. The findings highlight the importance of a patient-centered approach in managing CVD and provide additional evidence of the clinical benefits of MPFF in enhancing patient-important outcomes. However, the exact magnitude of this clinical impact remains to be confirmed through further investigation.</p> Protocol Registration <p>International Prospective Register of Systematic Reviews (PROSPERO), CRD42023476525.</p>