Biomaterials are omnipresent in today's healthcare services and are employed in various applications, including implants, sensors, healthcare accessories, and drug delivery systems. Unfavorable host immunological responses frequently jeopardize the efficacy of biomaterials. As a result, surface modification has received much attention in controlling inflammatory responses since it helps camouflage the biomaterial from the host immune system, influencing the foreign body response (FBR) from protein adsorption to fibrous capsule formation. Surfaces with controlled nanotopography and chemistry, among other surface modification methodologies, have effectively altered the immune response to biomaterials. However, the field is still in its early stages, with only a few studies showing a synergistic effect of surface chemistry and nanotopography on inflammatory and wound healing pathways. Therefore, this review will concentrate on the individual and synergistic effects of surface chemistry and nanotopography on FBR modulation and the molecular processes known to modulate these responses. This review will also provide insights into crucial research gaps and advancements in various tactics for modulating FBR, opening new paths for future research. This will further aid in improving our understanding of the immune response to biomaterials, developing advanced surface modification techniques, designing immunomodulatory biomaterials, and translating discoveries into clinical applications.