Background Arsenic (As) is a highly toxic and carcinogenic pollutant commonly found in soil and water, posing significant risks to human health and plant growth. Objective The objectives of this study to evaluate morphological, biochemical, and physiological markers, as well as ion homeostasis, to alleviate the toxic effects of As in sunflowers through the exogenous application of salicylic acid (SA), γ-aminobutyric acid (GABA), and their combination. Methods A pot experiment was conducted using two sunflower genotypes, FH-779 and FH-773, subjected to As stress (60 mg kg−1) to evaluate the effects of SA at 100 mg L−1, GABA at 200 mg L−1, and their combination on growth and related physiological and biochemical attributes under As stress. Results The study revealed that As toxicity had a detrimental effect on various growth parameters, chlorophyll pigments, relative water content, total proteins, and nutrient uptake in sunflower plants. It also led to increased oxidative stress, as indicated by higher levels of malondialdehyde (MDA) and hydrogen peroxide (H2O2), along with As accumulation in the roots and leaves. However, the application of SA and GABA protected against As-induced damage by enhancing the enzymatic antioxidant defense system. This was achieved through the activation of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) activities, as well as an increase in osmolytes. They also improved nutrient acquisition and plant growth under As toxicity. Conclusions We investigated the regulatory roles of SA and GABA in mitigating arsenic-induced phytotoxic effects on sunflower. Our results revealed a significant interaction between SA and GABA in regulating growth, photosynthesis, metabolites, antioxidant defense systems, and nutrient uptake in sunflower under As stress. These findings provide valuable insights into plant defense mechanisms and strategies to enhance stress tolerance in contaminated environments. In the future, SA and GABA could be valuable tools for managing stress in other important crops facing abiotic stress conditions.