Inflammation serves as a tissue’s defensive mechanism against harmful triggers, helping the body recover from abnormal pathological states to normal physiological homeostasis. However, chronic or uncontrolled inflammation may cause damage to the body and trigger a series of organic diseases. Macrophages, which are vital components of innate immunity, are crucial for maintaining tissue balance and modulating inflammation. They defend against pathogens, suppress inflammatory response and maintain tissue homeostasis through phagocytosis, the release of inflammatory mediators and phenotypic transformation [1]. When exposed to harmful bacterial infections or a hit occurs, the body initiates an inflammatory process, and macrophages will round up immune cells and release large amounts of cytokines for self-repair. However, excessively prolonged and uncontrolled inflammatory response disrupts the balance between M1 and M2 macrophages. This imbalance further promotes disease progression, including autoimmune diseases, diabetes, atherosclerosis, and obesity [2].

Drug discovery is a costly and lengthy endeavour with a high failure rate. Natural products with diverse structural profiles exhibit extensive biological efficacy and possess both safety and therapeutic promise. Natural products have emerged as crucial resources for drug development [3]. The 2020 NIH report indicates that 32% (441/1,393) of small-molecule pharmaceuticals authorized from January 1981 to September 2019 were natural products or their related compounds [4]. These compounds have demonstrated multifaceted therapeutic effects, including anti-inflammatory, antioxidant, and antiapoptotic effects [5]. Given the critical role of macrophages in inflammatory diseases and the superior anti-inflammatory activity of natural products, this review focuses on summarizing the remarkable potential of natural compounds in modulating macrophage polarization. In this paper, a critical review was conducted on the relevant data extracted from the PubMed and Web of Science databases, covering the period from 2020 to 2025 (the past five years). The search terms included “natural products”, “macrophage polarization”, and “inflammation”. The goal here is to offer new avenues for the treatment of inflammatory disorders (Fig. 1).