We assessed the effects of hypertonic saline solution (HSS) plus furosemide versus furosemide alone in patients with acute decompensated heart failure (ADHF). We searched four electronic databases for randomized controlled trials (RCTs) until June 30, 2022. The quality of evidence (QoE) was assessed using the GRADE approach. All meta-analyses were performed using a random-effects model. A trial sequential analysis (TSA) was also conducted for intermediate and biomarker outcomes. Ten RCTs involving 3013 patients were included. HSS plus furosemide significantly reduced the length of hospital stay (mean difference [MD]: -3.60 days; 95% confidence interval [CI]: -4.56 to -2.64; QoE: moderate), weight (MD: -2.34 kg; 95% CI: -3.15 to -1.53; QoE: moderate), serum creatinine (MD: -0.41 mg/dL; 95% CI: -0.49 to -0.33; QoE: low), and type-B natriuretic peptide (MD: -124.26 pg/mL; 95% CI: -207.97 to -40.54; QoE: low) compared to furosemide alone. HSS plus furosemide significantly increased urine output (MD: 528.57 mL/24 h; 95% CI: 431.90 to 625.23; QoE: moderate), serum Na (MD: 6.80 mmol/L; 95% CI: 4.92 to 8.69; QoE: low), and urine Na (MD: 54.85 mmol/24 h; 95% CI: 46.31 to 63.38; QoE: moderate) compared to furosemide alone. TSA confirmed the benefit of HSS plus furosemide. Due to the heterogeneity in mortality and heart failure readmission, meta-analysis was not performed. Our study shows that HSS plus furosemide, compared to furosemide alone, improved surrogated outcomes in ADHF patients with low or intermediate QoE. Adequately powered RCTs are still needed to assess the benefit on heart failure readmission and mortality.