Atherosclerosis refers to a unique form of chronic inflammatory anomaly of the vasculature, presented as rupture-prone or occlusive lesions in arteries. In advanced stages, atherosclerosis leads to the onset and development of multiple cardiovascular diseases with lethal consequences. Inflammatory cytokines in atherosclerotic lesions contribute to the exacerbation of atherosclerosis. Pharmacotherapies targeting dyslipidemia, hypercholesterolemia and neutralizing inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17, and IL-12/23) have displayed some promising although contradictory results. Moreover, adjuvants such as melatonin, a pluripotent agent with proven anti-inflammatory, anti-oxidative and neuroprotective properties, also display promises in alleviating cytokine secretion in macrophages through mitophagy activation. Here, we share our perspectives on this concept and present melatonin-based therapeutics as a means to modulate mitophagy in macrophages and, thereby, ameliorate atherosclerosis.