Usage of plant-based compounds has been increasing recently due to their unexpected efficacy in the mitigation of certain diseases, including atherosclerosis. The aims of this study are to investigate the potential anti-inflammatory and anti-oxidative effects of 14-deoxy-11,12-didehydroandrographolide (DDAGP), an Andrographis paniculata derivative, in C57BL/6J mouse model of atherosclerosis by determining relative NF-ĸB p65 and NOX-4 expression levels, in conjunction with biochemical profiling of plasma lipid and liver enzyme levels, in Poloxamer-407 (P-407) challenged C57BL/6J mouse model. Oral administration of DDAGP, with non-toxic concentration of 15 mg/kg/day, 30 mg/kg/day and 45 mg/kg/day, measurably reduced plasma lipid components, specifically LDL-c; but only the 45 mg/kg/day dose was conducive to significant TGL level reduction. Nevertheless, DDAGP did not significantly suppress the Atherogenic Index of Plasma (AIP) and the Atherogenic Coefficient (AC), suggesting that it lacks clinically significant anti-atherogenic ability. However, treatment of P-407 challenged mice with DDAGP significantly inhibited elevation of heart homogenate levels of NK-ĸB and NOX4 in a non-dose-dependent manner. Hence, even though DDAGP may not be an effective anti-atherogenic drug, it instead possesses marked anti-inflammatory and anti-oxidative potential. In conclusion, further research along these lines is warranted, with focus on DDAGP’s efficacy in the prophylaxis and management of inflammatory diseases.