Although the upregulation of enhancer of zeste homolog 2 (EZH2) expression and downregulation of long non-coding RNA (lncRNA) LET expression are known to be associated with cell apoptosis and proliferation, little is known about the interaction of EZH2 with lncRNA LET. The present study aimed to investigate the interaction of EZH2 and lncRNA LET, and the mechanism of human dermal fibroblast (HDF) proliferation and apoptosis. Tissue samples from 33 burn patients with second- and third-degree burns and 8 controls were collected. mRNA was extracted from the burn tissues for analysis. Isolated primary HDFs were treated with heat or transfected with LET overexpression vectors, and the cell functions and associated proteins in the HDFs were analyzed. Decreased lncRNA LET expression was detected in burn tissues compared with normal skin. Heat-treated HDFs exhibited a reduction in lncRNA LET expression and increase in EZH2 expression. LET gain-of-function experiments in primary HDFs revealed increases in cell proliferation, the proportion of cells in the S stage, and cyclin D1 and cyclin-dependent kinase 4 (CDK4) expression, and reductions in the percentage of apoptotic cells, the Bax/Bcl-2 ratio and caspase-3 expression. RNA immunoprecipitation and chromatin immunoprecipitation assays demonstrated the interaction of ZH2 with lncRNA LET, and of EZH2 with H3K27me3 in HDFs. Furthermore, a negative correlation between lncRNA LET and EZH2 expression was identified. It may be concluded that increased lncRNA-LET expression promoted cell proliferation and inhibited cell apoptosis via the cyclin D1-CDK4 and Bax/Bcl-2/caspase-3 signaling pathways, respectively. Furthermore, the inhibition of lncRNA LET may be regarded as an option for use in the healing of burns.