Small interfering RNA (siRNA) is an emerging therapeutic modality for a variety of diseases, including cancer, as siRNA can silence target genes in a sequence-specific manner. The effective delivery of siRNA remains a major challenge due to rapid clearance by macrophages in the systemic environment. Nonspecific interactions with the serum proteins in the bloodstream contribute to macrophage uptake, limiting circulation time, thereby reducing the effective delivery of siRNA to the target site. Here, we report the efficient delivery of siRNA to cancer cells using hyaluronic acid (HA)-coated cationic polymeric nanovector (PONI-Guan)/siRNA polyplexes. The guanidinium-functionalized polymers self-assemble with siRNA and enable cytosolic delivery. HA serves as a noninteracting protective shield on the polyplexes that prevent macrophage uptake in vitro. These nanovectors facilitate efficient siRNA delivery to 4T1 triple-negative breast cancer cells in vitro, with a 4:1 selectivity relative to macrophages. Further, HA-coated polyplexes demonstrated efficient STAT3 gene knockdown (~50%) in 4T1 cells. Intravenous administration of HA-coated polyplexes in 4T1 tumor-bearing mice showed significantly (~50%) decreased accumulation in clearance organs, in comparison to the PONI-Guan polyplexes. Collectively, HA-coated polyplexes provide an effective strategy for selective siRNA delivery to tumor cells while avoiding macrophage uptake.