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Abstract Non‐coding RNAs (ncRNAs) are important regulators of gene expression. They are expressed not only in cells, but also in cell‐derived extracellular vesicles (EVs). The mechanisms controlling their loading and sorting remain poorly understood. Here, we investigated the impact of TP53 mutations on the non‐coding RNA content of small melanoma EVs. After purification of small EVs from six different patient‐derived melanoma cell lines, we characterized them by small RNA sequencing and lncRNA microarray analysis. We found that TP53 mutations are associated with a specific micro and long non‐coding RNA content in small EVs. Then, we showed that long and small non‐coding RNAs enriched in TP53 mutant small EVs share a common sequence motif, highly similar to the RNA‐binding motif of Sam68, a protein interacting with hnRNP proteins. This protein thus may be an interesting partner of p53, involved in the expression and loading of the ncRNAs. To conclude, our data support the existence of cellular mechanisms associate with TP53 mutations which control the ncRNA content of small EVs in melanoma.