The dysregulation of YAP activity is implicated in abnormal organ size and the pathogenesis of diverse diseases, including cancer. However, the functional regulation of YAP activity by lncRNA-encoded peptides remains elusive. In this study, we report the identification of a small protein (93 aa) encoded by the lncRNA LINC01315. This small protein, termed YAPer-ORF, preferentially interacted with GNAQ/11 mutants to augment YAP activity. Mechanistically, YAPer-ORF was located in the nucleus and competed with YAP to bind the nuclear kinase PRP4K to hinder YAP phosphorylation. This decreased phosphorylation of YAP by YAPer-ORF promoted YAP retention in the nucleus and facilitated the expression of downstream target genes such as CCND1. In both cancerous and noncancerous models, YAPer-ORF prominently drove cell proliferation in a CCND1-dependent manner. Notably, cardiac-specific genetic knock-in of the human YAPer-ORF in mice significantly increased heart size through increased cardiomyocyte proliferation, underscoring the role of YAPer-ORF in cell proliferation. Moreover, treatment with an anti-YAPer-ORF neutralizing antibody effectively suppressed uveal melanoma growth, highlighting the therapeutic potential of targeting YAPer-ORF. These findings collectively establish YAPer-ORF as a critical regulator of YAP activity, further highlighting the disruption of YAPer-ORF activity as a potential therapeutic strategy against YAP-driven human cancers and developmental diseases.