Current models of X chromosome dosage compensation are usually framed by reference to how regulation in transcriptional level elevates the gene expression of the active X chromosome. This framework, however, might be oversimplified because regulation of gene expression can also act at the post-transcriptional level. Here, after a genome-wide survey, we find that autosomal genes are more likely subject to nonsense-mediated mRNA decay (NMD) than X-linked genes. Furthermore, we demonstrate that after NMD inhibition, balanced gene expression between X chromosome and autosomes is corrupted such that the global mean X/autosome gene expression ratio is decreased by 10–15%. Our results identify NMD as a post-transcription-level regulatory mechanism that contributes to the observed fine-tuning of X chromosome dosage compensation in mammals.