The antimicrobial activities of essential oils (EOs) isolated from Zizyphus lotus (ZL) and Ruta chalepensis (RC) harvested in Oran (north-west Algeria) were assessed against pathogenic clinical bacteria and fungi. The EOs were isolated using the steam distillation process, the phenolic and flavonoid contents were determined using colorimetric methods, and the chemical composition was carried out using GC-MS analysis. The antimicrobial activity was evaluated using agar disc diffusion and microdilution methods. The evaluation of the synergistic effect using the combination of Z. lotus (ZLEO) and R. chalepensis essential oils (RCEO) was done using the checkerboard assay. Effective extraction yields were determined for both plants, with an actual amount in RC than ZL. Concentrations of 8.47 ± 0 mg GAE/g DE and 8.56 ± 0.154 mg CE/g DE of total phenols were determined in ZLEO and RCEO, respectively. Thus, a chemotype of Diisooctyl-phthalate (80.343 %) was determined in ZLEO and the 2-Undecanone (13.236 %) in RC. Both plant EOs exhibited important antimicrobial activity against the selected multidrug-resistant human pathogens. The most potent effect was estimated against Proteus mirabilis, Salmonella enterica subsp. arizonae, and Hafnia alvei with growth inhibition zone diameters of 24.06 ± 0.12, 40.1 ± 0.1 and 40.16 ± 0.15 mm using ZLEO, respectively. Also, essential anti-Candida activity was estimated. ZLEO and RCEO did not exhibit either synergistic or additive effects, with fractional inhibition concentration index values greater than 2. Both plants exhibited significant antimicrobial effects alone, while in combination they did not exhibit a synergistic effect but an antagonistic one. Therefore, ZLEO and RCEO can be developed as natural antimicrobial agents in the medical and food industries to combat antimicrobial resistance.