Monocarboxylate transporter 4 (MCT4) is a membrane transporter of monocarboxylates that has been reported to play an important role in tumorigenesis and progression in several solid tumor types. The present study aimed to investigate its clinical significance in esophageal squamous cell carcinoma (ESCC). After obtaining and analyzing MCT4 mRNA expression data from The Cancer Genome Atlas (TCGA) database, the prognostic potential of MCT4 was evaluated by IHC analysis. The effect of the knockdown of MCT4 by shRNA was also evaluated using Cell Counting Kit-8 (CCK-8) and clonogenic assays, in order to determine whether MCT4 inhibition affected the proliferation and survival ability of ESCC cells. Flow cytometric analysis was used to evaluate apoptosis. Western blot analysis was performed to detect the expression levels of p-Akt, Bax, Bcl-2, cytoplasmic cytochrome c and cleaved caspase-3. MCT4 expression was associated with T stage (P=0.001), N stage (P=0.020) and formalin‑fixed and paraffin-embedded (TNM) stage (P=0.042). Kaplan-Meier survival analysis indicated that patients in the high-MCT4 group had a lower overall survival (OS) rate (P=0.001) and progression-free survival (PFS) rate (P=0.003). The univariate Cox regression analysis and multivariate Cox regression analysis results indicated that MCT4 is an independent predictor of OS (P=0.001 and 0.014) and PFS (P=0.004 and 0.046). Downregulation of MCT4 inhibited cell proliferation and increased apoptosis in vitro. The proliferation rate and clone numbers were decreased and apoptotic rates were increased in the sh-MCT4 groups (all P<0.05). Furthermore, MCT4 knockdown reduced the activation of Akt and increased Bax/Bcl-2 ratios, cytochrome c release and caspase-3 cleavage (all P<0.05). Consequently, MCT4 could serve as a promising biomarker for ESCC to identify patients with poor prognosis.