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Background and Aims: The mechanisms governing the progression of non‐alcoholic fatty liver disease (NAFLD) towards steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain elusive. Here, we evaluated the role of hsa‐miRNA‐21‐5p in NASH‐related hepatocarcinogenesis. Methods: Hepatic hsa‐miR‐21‐5p expression was evaluated in two cohorts of patients with biopsy‐proven NAFLD (n = 199) or HCC (n = 366 HCC and n = 11 NAFLD‐HCC). Serum/liver metabolomic profiles were correlated with hsa‐miR‐21‐5p in NAFLD obese patients. Wild‐type (WT) and Mir21 KO mice were fed a choline‐deficient, amino acid‐defined (CDAA) diet for 32 and 66 weeks to induce NASH and NASH‐HCC, respectively. Results: In obese individuals, hsa‐miR‐21‐5p expression increased with NAFLD severity and associated with a hepatic lipotoxic profile. CDAA‐fed WT mice displayed increased hepatic mmu‐miR‐21‐5p levels and progressively developed NASH and fibrosis, with livers presenting macroscopically discernible pre‐neoplastic nodules, hyperplastic foci and deregulated cancer‐related pathways. Mir21 KO mice exhibited peroxisome‐proliferator‐activated receptor α (PPARα) activation, augmented mitochondrial activity, reduced liver injury and NAS below the threshold for NASH diagnosis, with the pro‐inflammatory/fibrogenic milieu reversing to baseline levels. In parallel, Mir21 KO mice displayed reduced number of pre‐neoplastic nodules, hepatocyte proliferation and activation of oncogenic signalling, being protected from NASH‐associated carcinogenesis. The hsa‐miRNA‐21‐5p/PPARα pathway was similarly deregulated in patients with HCC‐ or NASH‐related HCC, correlating with HCC markers and worse prognosis. Conclusions: Hsa‐miR‐21‐5p is a key inducer of whole‐spectrum NAFLD progression, from simple steatosis to NASH and NASH‐associated carcinogenesis. The inhibition of hsa‐miR‐21‐5p, leading to a pro‐metabolic profile, might constitute an appealing therapeutic approach to ameliorate NASH and prevent progression towards HCC. [ABSTRACT FROM AUTHOR]