MicroRNA-34 (miR-34) family members are upregulated in the heart in response to stress. This study investigated the effects of miR-34 inhibition using a subcutaneously delivered seed-targeting 8-mer locked nucleic acid-modified antimiR (LNA-antimiR-34) in mouse models of heart disease. LNA-antimiR-34 attenuated cardiac remodelling and atrial enlargement and improved systolic function. Moreover, this study suggests that seed-targeting 8-mer LNA-antimiRs could be used to inhibit other miRNA seed families implicated in disease.