Background <p>Endophytes play an important role in improving the nutrient regime and growth status of host plants via symbiosis. Considering the importance of endophytes for maintaining good plant growth and development, we executed current study and investigated the effect of <i>S. indica</i> on watermelon plant growth, nutrient uptake efficiency and spatiotemporal variations in root-specific characteristics. Briefly, the surface sterilized seeds of three watermelon accessions were sowed on peat, perlite, and vermiculite media (3:2:1) in dark at 25&#xa0;°C, the photosynthetic photon flux density 880 µmol/m²/s, 28^◦C/21^◦C day/night temperature and 68% relative humidity was maintained. The plants were inoculated with the endophyte <i>S. indica</i> at one-to two-leaf stage except the control plants. <i>Serendipita indica</i> was cultivated on Potato Dextrose Agar at 28&#xa0;°C, and mass multiplied in 200&#xa0;ml Potato Dextrose Broth after inoculating mycelial discs from freshly grown PDA and incubated at 28&#xa0;°C with constant shaking at 150–200&#xa0;rpm. After filtration, the viable fungal homogenate was used as inoculant, two weeks later the root fungal structures were observed. The morphological/physiological and molecular perspectives were determined as described in material method section.</p> Results <p>The ZJU-accession (ZJU-197) with maximum colonization capacity has better plant growth (60.54%) and photosynthetic assimilation rate with maximum chlorophyll contents and more nutrients acquisition (N, P), thus making this symbiotic association helpful for watermelon plant physiological and morphological attributes. The endophyte <i>S. indica</i> upregulated Phosphomethylethanolamine N-methyltransferase domain proteins which are essential for the synthesis of secondary metabolites and participate in plant growth and nutrient uptake. Additionally, the colonized watermelon plants showed overexpression of dual affinity NRT1/PTR 7.3/6.3, similar to nitrate reductase and other metabolizing enzymes, thus making absorbed nutrients efficiently assimilated in the leaves to increase photosynthetic efficiency, resulting in biomass accumulation. Overexpression of genes facilitating nutrient uptake confirmed the influence of endophytes on nutrient acquisition in treated watermelon plants compared to that in untreated plants. The shared gene module enabled us to identify various auxin and secondary metabolite-regulated interlinked genes that contributed to watermelon plant growth induced by the <i>S. indica</i> inoculation.</p> Conclusion <p>Improved watermelon plant growth and nutrients availability have been elucidated from different physiological and molecular perspectives, and the phenotypic and genotypic variations in various plant traits are the definitive explanations for our hypothesis. These results emphasize the synergistic effects of <i>S. indica</i> on the nutritional status and growth characteristics of watermelon plants through the upregulation of certain secondary metabolites and other plant processes.</p>