Abstract: Background: Many studies have investigated the effect of alpha-lipoic acid (ALA) supplementation on lipid profile, and different results have been obtained from these studies. The current systematic review and dose-response meta-analysis was conducted to achive a strong conclusion about the effect of ALA supplementation on lipid profile including total cholesterol (TC), low- and high-density lipoprotein cholesterol (LDL, HDL) and triglycerides (TG). Methods: A systematic search was performed in PubMed, SCOPUS, ProQuest and Embase for randomized placebo-controlled human trials that examined the effect of ALA supplementation on lipid profile up to November 2020. The dose and duration of ALA supplementation for included studies were ranged between 300–1200 mg/d and 2–16 weeks respectively. Weighted mean differences (WMD) and 95% confidence intervals (CIs) were used to evaluate the effect size. Cochran’s Q and I2 tests were also used to assess between-study’s heterogeneity. In addition, subgroup analysis was performed to investigate potential sources of heterogeneity. Dose-response relationship was done using fractional polynomial modeling. Results: Among all eligible studies, 12 studies with a total number of 548 participants were selected. ALA caused a significant reduction on TC (WMD): −10.78 mg/dl, 95% CI: −20.81, −0.74, P=0.002), LDL (WMD: −10.88 mg/dl, 95% CI: −19.52, −2.24, P=0.014) and TG (WMD: −31.02 mg/dl, 95% CI: −49.63, −12.42, P<0.001). There was also a non-significant increaes in HDL concentrations. In addition, dose-response analysis showed a positive association between LDL (Pnon-linearity=0.026), TG (Pnon-linearity<0.001) and duration of intervention in a non-linear model. Conclusion: The present meta-analysis revealed the beneficial effects of ALA supplementation on TC, LDL and TG levels. Moreover, the beneficial effects of ALA supplementation on LDL and TG levels was duration-dependent.