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Background Modulation of the gut microbiome could favorably alter the hepatic venous pressure gradient (HVPG) in cirrhosis and portal hypertension (PH). Aim This meta-analysis was to evaluate the effects of microbiome-targeted therapies (MTTs) on HVPG in persons with cirrhosis and PH. Methods PubMed, The Cochrane Library, Embase, Web of Science and Scopus were searched for randomized clinical trials (RCTs) analyzing the effects on HVPG in people with cirrhosis who received MTTs. Clinical outcomes were pooled using RevMan5.3 software. A trial sequential analysis was applied to calculate the required information size and evaluate the credibility of the meta-analysis results. Results A total of six studies were included. MTTs were associated with a reduction of 1.22 mm Hg in HVPG (95% CI: -2.31, -0.14 mmHg, P = 0.03). Subgroup analysis showed a greater reduction with longer duration (-1.88 mmHg;95% CI: -3.23, -0.53; P = 0.006). In the trial sequential analysis of HVPG reduction, the cumulative Z curve crossed the traditional significance boundary without the achievement of required information size (330). Conclusions MTTs may be associated with a reduction in HVPG in patients with cirrhosis and PH. Microbiome-targeted therapies merit additional large-sample studies to define the efficacy of HVPG. Systematic review registration PROSPERO 2020: CRD4202021609.