Chronic inflammation is associated with the development and progression of several non-communicable diseases (NCDs), such as diabetes, cardiovascular disease, chronic kidney disease, cancer, and non-alcoholic fatty liver disease. Evidence suggests that pattern recognition receptors (PRRs) that identify pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) are crucial in chronic inflammation. Among the PRRs, Toll-like receptor 4 (TLR4) stimulates several inflammatory pathway agonists, such as the nuclear factor-κB (NF-κB), interferon regulator factor 3 (IRF3), and nod-like receptor pyrin domain containing 3 (NLRP3) pathways, that consequently trigger the expression of pro-inflammatory biomarkers, increasing the risk of NCD development and progression. Currently, studies have focused on the antagonistic potential of bioactive compounds, following the concept of food as a medicine, in which nutritional strategies may mitigate inflammation via TLR4 modulation. Thus, this narrative review discusses preclinical evidence concerning bioactive compounds from fruit, vegetable, spice, and herb extracts (curcumin, resveratrol, catechin, cinnamaldehyde, emodin, ginsenosides, quercetin, allicin, and caffeine) that may regulate the TLR4 pathway and reduce the inflammatory response. Bioactive compounds can inhibit TLR4-mediated inflammation through gut microbiota modulation, improvement of intestinal permeability, inhibition of lipopolysaccharide (LPS)-TLR4 binding, and decreasing TLR4 expression by modulation of microRNAs and antioxidant pathways. The responses directly mitigated inflammation, especially NF-κB activation and inflammatory cytokines release. These findings should be considered for further clinical studies on inflammation-mediated diseases.