Arsenic (As) contamination in soils poses serious risks to crop production and human health. While individual effects of vermicompost and arbuscular mycorrhizal fungi (AMF) on enhancing As tolerance in plants have been documented, their synergistic effects have not yet been explored. This study aimed to investigate the combined effects of these amendments in mitigating the toxic impacts of As on the quantity and quality of safflower (Carthamus tinctorius L.). Soil contamination with 80 mg kg− 1 of As decreased floret and seed yields due to the induction of oxidative stress and nutrient deficiency. The integrated amendment with vermicompost (8 % w/w) and Rhizophagus irregularis rather than their separate application improved the quantity and quality of florets and seeds under non-stress and stressful conditions. The combined treatment enhanced RWC (36.3 %), total chlorophyll (39.39 %), and carotenoid (29.12 %) contents, and increased the achene weight (27.8 %), seed yield (65.30 %), harvest index (53.57 %), floret yield (68.69 %), carthamidin content (34 %), and seeds oil percentage (41.36 %) under As stress. Applying vermicompost increased mycorrhizal colonization percentage (24.6 %) and reduced As bioavailability in the soil (18.95 %). The separate application of AMF and vermicompost reduced H2O2 and malondialdehyde contents in the leaves by enhancing superoxide dismutase and catalase activity, and proline accumulation. However, integrated amendment moderated these antioxidative responses. This treatment also caused the highest significant reductions in the translocation of As to the leaves (35.71 %) and grains (29.83 %), while improving the profile of essential nutrients (P, N, K, Fe, Mg, and Zn) in the roots, leaves, and seeds of As-stressed plants. Overall, this study highlights the potential of integrating AMF and vermicompost to improve crop productivity and nutritional quality while reducing As-associated health risks. However, further analysis on seed yield, oil components and floret colors in the field trials are required before recommendation of it for safflower cultivation in As-contaminated soils