The most significant threat to global food security is water scarcity. Despite the fact that vermicompost (an effective organic fertilizer rich in humic substances, macro- and micro-nutrients, earthworm excretions, beneficial soil microbes, plant growth hormones, enzymes) and effective microorganisms (EM; photosynthetic bacteria, lactic acid bacteria, yeasts, actinomycetes, fermenting fungi) have been recognized as powerful strategies for alleviating environmental stresses, their combined effect has not been studied. Herein, as a first investigation, we aimed to enhance wheat’s drought tolerance using an eco-friendly approach that combined vermicompost and EM. The study employed twelve treatments in a completely randomized design. The treatments included control, as well as single and combined applications of vermicompost and EM at three different irrigation levels (100%, 70%, and 30% of field capacity). Vermicompost and EM, applied singly or in combination, ameliorated drought-induced reduction in wheat growth and productivity by elevating photosynthetic pigment content, photochemical processes, Calvin cycle enzyme activity, net photosynthetic rate, transpiration rate, stomatal conductance, maximum quantum efficiency of PSII photochemistry, actual photochemical efficiency of PSII, electron transport rate, photochemical quenching coefficient, and effective quantum yield of PSII photochemistry. Additionally, adding vermicompost and/or EM improved wheat drought tolerance by increasing nutrient (nitrogen, phosphorus, potassium, iron, zinc, copper) acquisition, roots’ ATP content, H+-pump activity, and membrane stability index while lowering hydrogen peroxide content, lipid peroxidation, and electrolyte leakage. The new evidence demonstrates that combining vermicompost with EM sustains wheat drought tolerance by regulating photosynthetic efficiency, nutrient acquisition, root H+-pump activity, and membrane stability. Overall, utilizing vermicompost/EM is a novel approach to improving plant physiological responses and overcoming drought-related challenges.