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Biomaterials induced host immune responses, and fibrotic overgrowth remains a major barrier to the long-term function of medical devices and biomaterial consisting of tissue grafts. Screening new biomaterials to identify anti-fibrotic formulation requires in vivo testing, which is challenging to multiplex and remains a significant obstacle to progress in this field. Herein, we synthesized a combinatorial chemically modified hydrogel library and developed a cellular barcoding method that enables high-throughput multiplexed in vivo screening of 20 formulations in a single mouse and 100 formulations in a single non-human primate. Our screening method consists of implanting a mixture of biomaterials and each barcoded with human umbilical vein epithelial cells (HUVEC) from different individual donors. Single nucleotide polymorphism (SNP) genotypes of the cells were utilized as readouts using next-generation sequencing (NGS) to pair the material identity with material performance. Screening of the library using a xenogeneic transplantation model identified three novel lead hydrogel formulations (Z4-A10, Z1-A3, and Z2-A19) with improved anti-fibrotic properties that enable long-term cell viability. Z4-A10 was used to encapsulate human islets and validated for long-term glycemic control in an STZ-induced C57BL/6J diabetic mouse model. Leads, Z1-A3 and B2-A17, were further validated as immunomodulating coatings for medical-grade catheters to prevent fibrosis and occlusion, highlighting the translation of our screening approach and findings to other medical devices. Our results suggest that the developed cellular barcoding method and in vivo multiplexed screening technique can be leveraged to identify biomaterials for a wide range of clinical applications. Significantly, our newly discovered leads can improve the long-term performance of medical devices and encapsulated cell-based therapeutics.