Atherosclerosis (AS) is a chronic disease of the arterial wall. The role of lncRNAs in AS has been acknowledged. This study investigated the role of lncRNA plasmacytoma variant translocation 1 (PVT1) in AS via the MAPK/NF-κB pathway. Serum samples were collected from AS and non-AS patients. Serum levels of PVT1, CRP, IL-6, IL-1β, and TNF-α were determined. AS mouse model was established and transfected with si-PVT1. Levels of TG, TC, HDL, LDL, MAPK, NF-κB, MMP-2, MMP-9, TIMP-1, and macrophage content were detected. Human arterial vascular smooth muscle cells (HA-VSMCs) induced by 50 mg/mL oxLDL were transfected with si-PVT1 or oe-PVT1 and added with MAPK inhibitor U0126. Viability, apoptosis, cell cycle, colony formation and DNA replication were assessed. Levels of apoptosis-related proteins were detected. Consequently, PVT1 was highly expressed in AS patients. Silencing PVT1 decreased levels of TG, TC, LDL, IL-6, IL-1β, TNF-α, MMP-2, MMP-9, CRP, TIMP-1, MAPK, and NF-κB, increased HDL, reduced atherosclerotic plaques and macrophage content in mice, inhibited viability, clones and EdU positive rates in HA-VSMCs, but promoted apoptosis and cell cycle arrest. Inhibition of MAPK/NF-κB pathway suppressed proliferation and promoted apoptosis of HA-VSMCs while PVT1 overexpression facilitated AS development. Briefly, silencing PVT1 inhibited AS development by downregulating MAPK/NF-κB pathway.