ER stress is a crucial factor in the progression of vascular cell diseases. Notably, octanoic acid (OA; C8:0) and decanoic acid (DA; C10:0), prominent components of medium-chain fatty acids (MCFAs), may provide potential health benefits. However, their effects on vascular smooth muscle cells (VSMCs) remain unknown. Given the link between ER stress and vascular cell pathological conditions, the primary goal of this research is to investigate the protective effects of OA and DA against ER stress induction in rat aortic smooth muscle cells (RASMCs). To achieve this objective, RASMCs were pretreated with OA and DA at concentrations of 250 and 500 μM for 24 h. Subsequently, the cells were exposed to 1 μg/mL of tunicamycin, an ER stress inducer, for an additional 24 h. Apoptosis was assessed using DAPI staining, while DCFH2-DA probe was used to measure ROS levels. Furthermore, the gene expression of ER stress markers, such as CHOP, GRP78, ATF4, and eIF2α, as well as contractile markers like αSMA and MYH11, was assessed using real-time reverse transcription polymerase chain reaction. Moreover, the αSMA protein level was measured using immunocytochemistry techniques. The study revealed that OA and DA significantly mitigated cell death caused by tunicamycin, decreased ROS production, and inhibited the gene expression of ER stress markers (CHOP, GRP78, and eIF2α). Notably, OA and DA also inhibited the expression of contractile genes (α-SMA and MYH11) and reduced the number of α-SMA-positive cells in tunicamycin-treated RASMCs. These findings indicate that OA and DA offer protection against ER stress-stimulated cell death and ROS generation in VSMCs, thereby supporting their potential therapeutic applications for safeguarding these cells.