Osteosarcoma (OS) is the most common form of primary malignant bone cancer in adolescents. Over the years, OS prognosis has greatly improved due to adjuvant and neoadjuvant (preoperative) chemotherapeutic treatment, increasing the chances of successful surgery and reducing the need for limb amputation. However, chemotherapeutic treatment to treat OS is limited by off-target toxicities and requires improved localization at the tumor site. Collagen, the main constituent of bone tissue, is extensively degraded and remodeled in OS, leading to an increased availability of denatured (monomeric) collagen. Collagen hybridizing peptides (CHPs) comprise a class of peptides rationally designed to selectively bind to denatured collagen. In this work, we have conjugated CHPs as targeting moieties to water-soluble -(2-hydroxypropyl)methacrylamide (HPMA) copolymers to target OS tumors. We demonstrated increased accumulation of collagen-targeted HPMA copolymer-CHP conjugates compared to nontargeted HPMA copolymers, as well as increased retention compared to both nontargeted copolymers and CHPs, in a murine intratibial OS tumor model. Furthermore, we used microcomputed tomography analysis to evaluate the bone microarchitecture and correlated bone morphometric parameters (porosity, bone volume, and surface area) with maximum accumulation () and accumulation at 168 h postinjection () of the copolymers at the tumor. Our results provide the foundation for the use of HPMA copolymer-CHP conjugates as targeted drug delivery systems in OS tumors.