Excessive use of pesticides has caused agricultural and environmental hazards. Microbial inoculation is an alternate to pesticides for confronting pathogens and is an environmental friendly approach. Endophytes are beneficial microbes and biologically safe for inducing tolerance in plants. Hence, the current research was conducted to evaluate endophytes potential in wheat against drought stress and rust diseases. Fifty genotypes of wheat were sown under Randomized Complete Block Design (RCBD) in field conditions for evaluation against rust diseases and drought conditions. The drought stress was given to the wheat genotypes by skipping the irrigation at flowering and grain filling stage for drought resistance whereas all genotypes were also inoculated against rust diseases through natural and artificial method at tillering and heading stage. Data regarding drought stress were recorded on the basis of different growth parameters viz. number of grains per spike, 1000-grain weight (g), number of productive tillers m2, biological yield (gm-2), grain yield (gm-2), harvest index % and percent yield reduction, drought tolerance indices like mean productivity (MP), tolerance index (TOL) and stress susceptibility index (SSI). Data regarding final disease severity percentage, area under disease progress curve and coefficient of infection were recorded for rust diseases. Kohsar-95 and Parwaz-94 exhibited most drought sensitive genotypes while two leaf rust (Faisalabad-85, Aas-02) and two yellow rust genotypes viz. Fareed-06 and Shafaq-06 expressed susceptible response. Plant samples for endophytes were collected from desert areas (Cholistan, Thar and Rohi) of Pakistan. The endophytes were isolated, identified and purified in Plant Mycology Lab. on sterilized Potato Dextrose Agar media (PDA). The in-vitro efficacy of endophytes was evaluated in test tubes containing 0.3% agar concentration. The wheat seed was sown in test tube containing distilled water along with fungal spore suspensions (1×106/ml) and incubated at 28±2oC. The root and shoot length was measured after 4 days of interval. The four endophytes expressed significant results were used for further studies. Spore suspensions of these endophytes were prepared and their concentrations were observed through haemocytometer. Seeds of disease and drought susceptible wheat genotypes were inoculated by dipping in spore suspension and sown in field under factorial RCBD. Inoculated susceptible wheat genotypes exhibited the tolerance against drought and rust diseases. The endophyte Piriformospora indica showed significant increase in grain yield 15.4% of drought sensitive genotypes followed by Colletotrichum lindemuthianum, Trichoderma viride, and Acremonium lolii 11.3 %, 8.1 % and 7.5 % respectively. Similarly, for leaf and yellow rust diseases P. indica also exhibited statistically significant increase in grain yield 17.5% and 12.3%, respectively followed by Trichoderma spp. (13.7 % and 10.6 %). Colletotrichum spp. and Acremonium spp. showed (7.1%, 6.2%) as well as (8.2%, 4.2%) under leaf rust and yellow rust conditions respectively.