Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA_1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA_1/3 antagonism using the small molecule Ki16425. We show that LPA_1/3 inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA_1/3 blockade enhanced the percentage of non-inflammatory, Ly6C^low monocytes and CD4⁺ CD25⁺ FoxP3⁺ T-regulatory cells. Finally, we demonstrate that LPA_1/3 antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA_1/3 receptors may prove a promising approach to diminish atherosclerosis development.