The receptor tyrosine kinase HER3 is well established as a compelling therapeutic target in numerous cancers, including ovarian cancer. HER3 potently activates the PI3K/Akt pro-survival pathway, mediates drug resistance, and is implicated in cancer progression and poor clinical outcomes. Yet, conventional small molecule- and monoclonal antibody-based approaches have so far failed to yield a widely used therapeutic that directly targets HER3. Here, we investigated a novel approach involving specific, multivalent engagement of HER3 with affibody molecules as an alternative to existing therapeutics. We established that multivalent HER3-targeted affibodies more effectively inhibit neuregulin 1β-mediated HER3 activation compared to monovalent affibodies; these multivalent ligands induced rapid and prolonged HER3 downregulation, indicating a potentially valuable mechanism of action to limit HER3-mediated pro-mitogenic signaling and acquired resistance. HER3-targeted affibodies also proved highly amenable to molecular engineering approaches, as modulation of linker length, valency, and albumin binding domain (ABD) fusion placement allowed for robust retention of ligand bioactivity. We further report significant mechanistic evidence supporting HER3 downregulation as a highly specific phenomenon prompted by HER3 sequestration by multivalent ligands. Most importantly, we show that both monovalent and bivalent HER3-targeted affibody-ABD fusion proteins significantly reduce tumor burden in an adriamycin-resistant ovarian cancer model in mice. Overall, these data serve as compelling evidence for HER3 multivalent ligands as promising experimental therapeutics for the treatment of ovarian cancer as single agents as well as in combination with other drugs. Further, HER3 affibodies represent a promising template for development of targeted therapies or drug conjugates for more powerful ovarian cancer therapy in the future.