Hyperoxia-induced lung injury (HILI) tends to develop bronchopulmonary dysplasia. Adipose-derived mesenchymal stem cell (ADMSC)-derived extracellular vesicles (EVs) hold great promise in alleviating lung injury. This study explored the mechanism of ADMSC-EVs in HILI. ADMSC-EVs were isolated and identified. The murine and cell models of HILI were established. HILI mice and cells were pre-treated with ADMSC-EVs. The lung dry/wet ratio, pathological structure, apoptosis, and inflammation of HILI mice were measured. The viability, apoptosis, and oxidative stress of HILI cells were measured. The internalization of EVs in lung and cells was observed by fluorescence labeling. The binding relationships between miR-21-5p and SKP2, and Nr2f2 and C/EBPα were analyzed. The binding of SKP2 and Nr2f2 and the Nr2f2 ubiquitination level were detected. ADMSC-EVs exerted preventive effects on HILI mice, evidenced by reduced lung dry/wet ratio, inflammation, and apoptosis in HILI mice. In vitro, EVs enhanced HILI cell viability and reduced apoptosis, inflammation, and oxidative stress. EVs carried miR-21-5p into lung cells to upregulate miR-21-5p expression and thereby target SKP2. SKP2 bound to Nr2f2 and promoted its ubiquitination degradation. EVs inhibited the binding of Nr2f2 and C/EBPα and further suppressed C/EBPα transcription. Collectively, ADMSC-EVs carrying miR-21-5p alleviated HILI via the SKP2/Nr2f2/C/EBPα axis.