Polyamines (PAs) are plant growth regulators that attenuate the destructive impacts of water deficit on sesame plants, particularly in arid regions under abrupt climate change. Limited information is available on the physiological, biochemical, anatomical, and agronomic responses of sesame to exogenous application of PAs under water deficit under field conditions. Thus, a two-season field trial was carried out to assess the impact of exogenously sprayed spermine (Spm), spermidine (Spd), and putrescine (Put) on physio-biochemical and anatomical parameters and their influences on agronomic performance and crop water productivity of sesame plants. The sesame plants were assessed under three irrigation regimes; full irrigation (100% ETc), mild drought (75% ETc), and severe drought (50% ETc) conditions. Drought stress displayed negative impacts on all evaluated parameters. However, exogenously applied Pas, especially Put, restricted the destructive effects of water deficit. The application of PAs exhibited highly significant enhancement in photosynthetic pigments (chlorophyll a, b, and carotenoids), gas exchange (net photosynthetic rate, stomatal conductance, and rate of transpiration), water relations (relative water content, membrane stability index, excised leaf water retention), and plant nutrient content (N, P, and K) compared to untreated plants, particularly under severe drought stress. Moreover, PA application displayed highly significant amelioration in osmoprotectants (free proline, soluble sugars, α-Tocopherol, ascorbate, and glutathione), and antioxidant enzyme activities (catalase, peroxidase, superoxide dismutase, ascorbate peroxidase, and glutathione reductase). In addition, foliar nourishing with PAs exhibited a highly significant reduction in oxidative stress markers (malondialdehyde, electrolyte leakage, superoxide, and hydrogen peroxide). These positive impacts of PA application under drought stress were reflected in highly significant improvement in anatomical characteristics (midrib length and width, vascular bundle length and width, thickness of phloem, xylem and collenchyma, vessel diameter, and number of xylem rows in midvein bundle), and yield-related traits (plant height, leaf area, number of capsules per plant, 1000-seed weight, seed yield, and oil content). Consequently, exogenous application of PAs (in particular, Put) could be exploited to enhance the crop water productivity and yield traits of sesame plants under low water availability in arid regions.