Introduction: Antibiotic resistance is a global problem that threat the public health. New patterns of antimicrobial resistance emerge daily which get through the international boundaries and easily spread. The aim of this study is to evaluate the activity of Euphorbia trigona rubra leaves crude extract on this drug resistance bacteria’s. Materials and methods: This study was carried out in natural product laboratory in collaboration with Microbiology Laboratory. Antimicrobial sensitivity patterns of the bacteria were done by using Kirby Bauer Disc Diffusion method. Antibiotics which were tested in congruent with the crude extract include Augmentin (10 μg), Amoxicillin (10 μg), Ampicillin (10 μg), Cefixime (30 μg), Ticarcillin (30 μg), Ceftazidime (30 μg), Azithromycin (15 μg), Gentamycin (10 mcg), Ciprofloxacin (10 μg), Trimethoprim-Sulfamethaxazole (10 μg), Doxycycline (30 μg), Chloramphenicol (30 μg), and Rifampicin (30 μg). Results: Euphorbia trigona rubra leaves crude extract has shown a significant activity of 21.33±0.55 mm when compared to the drug (4.63±0.71 mm, 7.33±0.55 mm, 4.00±0.06 mm, 4.58±0.21 mm, 7.11±1.00 mm, 5.97±0.87 mm, 4.63±0.71 mm, 7.33±0.55 mm, 5.00±0.06 mm, 5.58±0.21 mm, 5.97±0.87 mm, 4.63±0.71 mm, and 9.13±0.55 mm) at 500 µg/mL, respectively that the bacterium was resistance to, this shows that the crude extract from the leaves of this cactus plant has an effective activity for resistance bacteria and should be considered as an agent in the pharmaceutical industries.