Oxidative stress perturbs lipid homeostasis and contributes to metabolic diseases. Though ignored compared to mitochondrial oxidation, the endoplasmic reticulum (ER) generates reactive oxygen species requiring antioxidant quality control. Using multi-organismal profiling featuringDrosophila, zebrafish, and mammalian cells, here we characterize the paraoxonase-like APMAP as an ER-localized protein that promotes redox and lipid homeostasis and lipoprotein maturation. APMAP-depleted mammalian cells exhibit defective ER morphology, elevated ER and oxidative stress, lipid droplet accumulation, and perturbed ApoB-lipoprotein homeostasis. Critically, APMAP loss is rescued with chemical antioxidant NAC. Organismal APMAP depletion inDrosophilaperturbs fat and lipoprotein homeostasis, and zebrafish display increased vascular ApoB-containing lipoproteins, particles that are atherogenic in mammals. Lipidomics reveals altered polyunsaturated phospholipids and increased ceramides upon APMAP loss, which perturbs ApoB-lipoprotein maturation. These ApoB-associated defects are rescued by inhibiting ceramide synthesis. Collectively, we propose APMAP is an ER-localized antioxidant that promotes lipid and lipoprotein homeostasis.Key findings summaryAPMAP localizes primarily to the ER network in human cells andDrosophilafat body tissue, and is a type II integral membrane proteinLoss of APMAP orDrosophilaAPMAP (dAPMAP) causes ER membrane expansion, elevates CHOP-associated ER stress, promotes LD accumulation, and alters ApoB-lipoprotein secretionAPMAP-depleted cells and dAPMAP-depletedDrosophilafat tissue exhibit defective redox homeostasis; phenotypes associated with APMAP loss are rescued by antioxidant NACZebrafish-based LipoGlo reporter reveals that loss ofapmapin zebrafish causes increased vascular ApoB-containing lipoproteinsLipidomic profiling indicates that APMAP loss reduces PUFA-phospholipids and elevates intracellular ceramides, which perturbs ApoB maturation