Acute low-tone hearing loss (ALHL) is a common clinical disease and was first proposed by Abe in 1981 as sensorineural hearing loss confined to low frequencies. The best strategy for initiating medication is still unclear, as the superiority of steroids and diuretics is still debated, and combination therapy might yield additional benefits. However, no study regarding combination therapy has been published. The objective of this study was to evaluate the efficacy of steroid therapy versus combination therapy of diuretics with steroids by conducting a systematic review with a meta-analysis and trial sequential analysis (TSA). Studies enrolling patients with a diagnosis of acute low-tone hearing loss were considered eligible. After searching the PubMed, Cochrane Library, Embase, Scopus and Web of Science databases from inception to 31 December 2021, five studies including 433 patients were enrolled. Overall, the comparison between combination therapy with steroids and diuretics and single-modality treatment with steroids (OR, 1.15; 95% CI, 0.51 to 2.59; p = 0.74; I2 = 34%) and the comparison between combination therapy and treatment with diuretics alone (OR, 1.73; 95% CI, 0.93 to 3.23; p = 0.09; I2 = 5%) showed that combination therapy did not confer significant benefits when compared to single-modality treatments. A trial sequential analysis (TSA) showed conclusive nonsignificant results of the comparison between the combination of steroids and diuretics and a single-modality treatment. In conclusion, we reported that the combination of steroids and diuretics did not yield significant benefits when compared to single-modality treatment with steroids or diuretics. We suggest that treatment should be initiated with steroids or diuretics alone to avoid potential adverse effects.