Resuscitation from shock generally targets macrohemodynamic parameters. However, this approach may not be followed by improved microcirculation and carries a risk of fluid overload. We aimed to evaluate the efficacy of tissue-perfusion-guided therapy (TP-GT) compared with standard care in adult patients with shock. Following the PRISMA 2020 guidelines, we searched MEDLINE, Embase, and CENTRAL on October 26, 2025, for randomized controlled trials (RCTs) comparing TP-GT to standard therapy. The protocol was prospectively registered on PROSPERO (CRD420251163043). The primary outcomes were 30-day and 90-day mortality. Secondary outcomes included intensive care unit length of stay (ICU LOS), hospital length of stay (HLOS), fluid administration volumes, fluid balances and organ support requirements. The meta-analyses were performed using the random-effect model, and the risk of bias was assessed using the RoB2 tool. Eight RCTs were analyzed, comprising 2,394 patients. TP-GT did not significantly reduce either 30-day mortality (Risk Ratio [RR] 0.96; 95% CI 0.83–1.10; P  = 0.49) or 90-day mortality (RR 0.94; 95% CI 0.82–1.07; P  = 0.17) compared to standard care. However, patients managed with TP-GT were associated with a shorter ICU LOS (Mean Difference [MD] -0.72 day; 95% CI -1.42 to -0.01; P = 0.048), although this finding proved fragile in sensitivity analyses. Furthermore, TP-GT significantly reduced the volume of fluid administered through the first 6–8 hours of resuscitation (MD -466.95 mL; 95% CI -917.17 to -16.72; P = 0.046). It promotes personalized fluid stewardship by significantly reducing early fluid administration and may be associated with shorter ICU LOS.