Excessive demand for translation and protein folding in the endoplasmic reticulum (ER) can cause ER stress in plants. Here, we show that CALRETICULIN 1 (CRT1) and CRT2 are critical components in the accumulation of VESICLE‐ASSOCIATED MEMBRANE PROTEIN 721 (VAMP721) and VAMP722 during ER stress responses. We show that CRT2 interacts with VAMP722 and that CRT1/2 post‐translationally maintain elevated VAMP721/722 levels under ER stress. The greater growth inhibition in VAMP721/722‐deficient plants, induced by tunicamycin, suggests that plants under ER stress maintain physiological homeostasis, at least in part, by regulating VAMP721/722 levels, as VAMP721/722 are known to participate in various biological processes.