Spinach (Spinacia oleracea L.) is a highly nutritious, desirable green leafy vegetable, which is less tolerant to drought. This study was conducted to establish the impact of a natural bio-stimulant consisting of a mixture of fish protein hydrolysates and kelp extract (trade name, Xcell Boost) on the physiological and biochemical responses as well as vegetative growth of spinach (Spinacia oleracea L.) under different water levels (100% (full irrigation), 50% (mild drought stress) and 30% (severe drought stress) water holding capacity). Bio-stimulant application at any strength (single, BX1 or double, BX2) had no effect on the photochemical reactions. The application of bio-stimulant at double strength concentration (BX2) increased the chlorophyll and carotenoid contents, as well as the activities of antioxidative enzymes, ascorbate peroxidase (APX) and guaiacol peroxidase (GPX), under drought stress. Application at single strength (BX1) increased the normalised difference vegetation index (NDVI), stomatal conductance, accumulation of osmoprotectants (proline and total soluble sugars) and reduced electrolyte leakage under drought stress. Furthermore, bio-stimulant applications at either concentration induced remarkable increases in plant height, leaf area, stem dry weight, root length and root moisture. Under BX2, APX and stomatal conductance positively correlated with stem dry weight, while root length positively correlated with total chlorophyll content. These results show that Xcell Boost is a highly advantageous bio-stimulant for increasing the tolerance of spinach to drought stress, which can most likely benefit other crops grown in semi-arid and arid areas.