Prevention of atherosclerotic plaque formation, reduction in plaque burden and stabilization of a vulnerable plaque are of therapeutic significance in decreasing the incidence of acute events. Initially, we found an imbalance between the inflammation and reparative process, leading to plaque instability. The findings supported the critical role of TLR4 and TREM-1 in underlying pathophysiology of chronic inflammation, atherosclerotic plaque formation and plaque instability. Thus, we examined the effect of the selective inhibitors of TREM-1 (LR-12) and TLR4 (TAK242) in a microswine model of carotid artery atherosclerosis. Hypercholesterolemic Yucatan microswine were treated with a control vehicle and TREM-1 or TLR4 inhibitor at the time of intimal injury and were sacrificed after 5–6 months. Optical coherence tomography (OCT) showed plaques with thick fibrous cap and occluded arteries in the controls. Radiological evaluation of carotid arteries revealed decreased neointimal hyperplasia and plaque formation with treatment using the TREM-1 inhibitor compared to the scrambled peptide group. There was no significant effect of TAK242 when dissolved in 30% ethanol. However, TAK242 dissolved in a clinically relevant vehicle significantly decreased the plaque size and enhanced plaque stabilization. Histomorphologically, there was neointimal hyperplasia with significantly increased inflammation and elastin degradation in the controls compared to the inhibitor groups on H&E and Movat pentachrome staining. The gene and protein expression for the markers of plaque vulnerability, including MMP-7, IL-6, IL-12/23, and CD36, were significantly decreased with treatment using the TREM and TLR4 inhibitors (dissolved in clinically relevant vehicle) compared to individual vehicle control. The findings of this study support the therapeutic efficacy of inhibiting either TLR4 or TREM-1 signalling alone or in combination in attenuating atherosclerotic plaque vulnerability, reducing plaque burden and thus preventing the occurrence of transient ischaemic attack and stroke.