Nickel (Ni) bioavailable fraction in the soil is of utmost importance because of its involvement in plant growth and environmental feedbacks. High concentrations of Ni in the soil environment, especially in the root zone, may retard plant growth that ultimately results in reduced plant biomass and yield. However, endophytic microorganisms have great potential to reduce the toxicity of Ni, especially when applied together with zeolite. The present research work was conducted to evaluate the potential effects of an endophytic bacterium Caulobacter sp. MN13 in combination with zeolite on the physiology, growth, quality, and yield of sesame plant under normal and Ni stressed soil conditions through possible reduction of Ni uptake. Surface sterilized sesame seeds were sown in pots filled with artificially Ni contaminated soil amended with zeolite. Results revealed that plant agronomic attributes such as shoot root dry weight, total number of pods, and 1000-grains weight were increased by 41, 45, 54, and 65%, respectively, over control treatment, with combined application of bacteria and zeolite in Ni contaminated soil. In comparison to control, the gaseous exchange parameters (CO2 assimilation rate, transpiration rate, stomatal- sub-stomatal conductance, chlorophyll content, and vapor pressure) were significantly enhanced by co-application of bacteria and zeolite ranging from 20 to 49% under Ni stress. Moreover, the combined utilization of bacteria and zeolite considerably improved water relations of sesame plant, in terms of relative water content (RWC) and relative membrane permeability (RMP) along with improvement in biochemical components (protein, ash, crude fiber, fat), and micronutrients in normal as well as in Ni contaminated soil. Moreover, the same treatment modulated the Ni-stress in plants through improvement in antioxidant enzymes (AEs) activities along with improved Ni concentration in the soil and different plant tissues. Correlation and principal component analysis (PCA) further revealed that combined application of metal-tolerant bacterium Caulobacter sp. MN13 and zeolite is the most influential strategy in alleviating Ni-induced stress and subsequent improvement in growth, yield, and physio-biochemical attributes of sesame plant.