Background: Water use efficiency (WUE) is becoming a decisive factor for agricultural expansion to face water shortage. To meet the needs of high population density in Egypt, we have to use modern irrigation systems and new cultivation technologies. The current study is aiming to apply grafting technique for ameliorating the impact of deficit water on cantaloupe productivity and fruit quality. Two commercial cultivars (Ideal and Veleta) were grafted on two rootstocks (Cobalt and Strong-Tosa) and self-grafting. The seedlings were treated with three different irrigation levels: 100, 75, and 50% of Class A pan Evapotranspiration (ETc). Results: The results showed that moderate irrigation level (75% ETc) increased the early yield, fruits number, by 15.3 and 17.4%, respectively, compared to control irrigation treatment (100% ETc). No significant variation was found concerning total yield between 100 and 75% ETc, so this led to an increase in WUE of moderate irrigation level (75% ETc) by 34.3%, compared to control irrigation treatment (100% ETc). Increasing deficit levels up to 50% ETc reduced the total yield by 47.4%, but it increased the WUE by 8.8%, compared to the non-deficit irrigation level (100% ETc). Meanwhile, grafting both cultivars on Cobalt rootstock improved the fruit number, total yield, and WUE by 39.2%, 26.9%, and 24.1%, respectively when irrigated with the moderate irrigation level (75% ETc), as compared to the non-grafted plants which recorded the highest decrease when irrigated with deficit irrigation level (50% ETc). Conclusion: Finally, the combination treatments of Ideal/Strong-Tosa, Veleta/Cobalt, or Ideal/Cobalt irrigated with moderate irrigation level (75% ETc) increased the WUE by 97.3, 83.4, and 65%, respectively, compared to the control treatment (non-grafted plants of the same cv. at 100% ETc) and recorded higher flesh thickness, TSS and firmness.