Linker histone H1 stabilizes chromatin, but the functions of its variants remain incompletely understood. Among the seven somatic H1 variants, H1-10 has the minimal sequence similarity to others, suggesting a distinct biological role. Here, we show that H1-10, unlike other somatic variants, localizes predominantly to the nucleolus, where it promotes nucleolar assembly through liquid-liquid phase condensation and enhances RNA polymerase I occupancy at ribosomal DNA (rDNA). This results in amplified rRNA transcription and increased global protein synthesis. H1-10 is upregulated across multiple cancer types and, in prostate cancer, selectively augments E2F3 translation, thereby activating a broad cell-growth transcriptional program. Through structure-based screening, we identified first-in-class small-molecule inhibitors that disrupt H1-10 DNA binding and nucleolar localization, effectively suppressing prostate tumor growth without overt toxicity. Lead optimization produced compound CN27 (IC₅₀ = 180 nM; >100-fold selectivity of H1-10 over H1-1/H1-6), which demonstrated potent efficacy in castration-resistant prostate cancer models. Collectively, our findings uncover a critical role of H1-10 in ribosome biogenesis and oncogenic translation, providing proof-of-concept for pharmacological targeting of histone variants.