(1) Background: The EndoSequence BC Sealer HiFlow (Brasseler, Savannah, GA, USA) has recently been introduced in clinical applications. Thus, the aims of the present study are to determine its biocompatibility in vivo and to examine its ability to drive macrophage polarization in vitro and in vivo. (2) Methods: HiFlow was implanted into rat connective tissue for 7, 30 and 150 days. The microstructures and elemental compositions were determined by scanning electron microscopy-energy-dispersive X-ray spectroscopy (SEM-EDX). Hematoxylin–eosin, immunofluorescence, RT–qPCR and flow cytometry were used to elucidate the effects on inflammatory responses and macrophage polarization. (3) Results: SEM-EDX revealed the formation of surface hydroxyapatite crystal layers. Histological evaluation showed that HiFlow exhibited long-term biocompatibility because it decreased inflammatory responses and reduced the number of macrophages over time; however, tissue necrosis was observed in all the groups. RT–qPCR verified that HiFlow regulated the expression of inflammatory factors to inhibit the inflammatory response. Immunofluorescence analysis performed on in vivo samples revealed that HiFlow promoted M2-like macrophage polarization, and these results were confirmed by flow cytometry in vitro. (4) Conclusion: After 150 days of investigation, HiFlow was considered biologically acceptable, and the formation of apatite crystal layers and the promotion of M2-like macrophage polarization may contribute to its favorable biocompatibility.