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Orphan genes, which encode species-specific proteins, are common but are rarely investigated. The SARS-CoV-2 orphan gene, ORF10, has been understudied; in vitro work suggests it may modulate innate immunity. Whether ORF10 influences COVID-19 outcomes in humans remained unknown. Here, analyzing millions of SARS-CoV-2 genomes, we find ORF10 sequences are identical to ancestral Wuhan-Hu-1 haplotype. In all variants of concern, <5% of genomes carry any ORF10 mutation. Despite limited statistical power due to the sparsity of mutated sequences, four ORF10 mutations were associated with less severe clinical outcomes in COVID-19 patients: three affect protein structure, one alters RNA structural dynamics. No mutations were linked to increased severity. ORF10 transcript levels in humans and human models are conditionally discordant from other SARS-CoV-2 genes. ORF10 expression in A549 and 293T cells significantly perturbs oxidative phosphorylation gene expression, disrupts immune gene networks, and shifts expression of 14 novel human transcripts. ORF10 is present in multiple Betacoronavirus pandemicum strains, but absent from SARS-CoV-1-like strains. We propose that this strain-restricted orphan gene contributes to severe COVID-19 in humans, with implications for future therapeutic strategies. These findings underscore the importance of studying recently evolved, potentially overlooked, viral orphan genes as a standard approach in pandemic preparedness.