Obeticholic acid (OCA) is currently approved as a second-line therapy for primary biliary cholangitis (PBC) and has emerged as a promising candidate for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). This systematic review and meta-analysis evaluated the effects of OCA on lipid profiles and clinical outcomes in patients with PBC and MASH. A comprehensive search of five major databases was conducted from inception to February 21, 2022. Six randomized controlled trials (RCTs) were included, three investigating OCA in PBC and three in MASH. Changes in lipid profiles from baseline were compared between OCA and placebo groups. Efficacy outcomes were analyzed separately for PBC and MASH, while safety outcomes included pruritus, gastrointestinal disturbances, and headache. All analyses were performed using RevMan. Compared with placebo, OCA treatment was associated with a significant increase in low-density lipoprotein cholesterol (LDL-C) (standardized mean difference [SMD] = 0.39; 95% confidence interval [CI], 0.15–0.63) and a significant decrease in high-density lipoprotein cholesterol (HDL-C) (SMD = –0.80; 95% CI, –1.13 to –0.47). OCA demonstrated superior efficacy over placebo in both primary and secondary outcomes for PBC and MASH. However, the incidence of pruritus was significantly higher among patients receiving OCA compared with placebo (risk ratio = 1.78; 95% CI, 1.42–2.25). In conclusion, OCA provides greater efficacy than placebo in the treatment of PBC and MASH. Nevertheless, its use is associated with unfavorable lipid profile changes, including increased LDL-C and decreased HDL-C, underscoring the need for careful lipid monitoring during therapy.