Ziziphus spina-christi (L.), a traditional Arabian medicinal herb, has been used by Egyptians (Bedouin and Nubian) to treat inflammatory symptoms and swellings, pain, and heat since long. We aimed to investigate whether Ziziphus spina-christi leaf extract (ZSCLE) exerted a myocardial and renal protective effect on mice in which sepsis had been induced with cecal ligation and puncture (CLP). Male C57BL/6 mice were divided randomly into six groups (n = 7): sham-operated group, sham-operated mice treated with ZSCLE (300 mg/kg), CLP-induced sepsis group, ZSCLE (100 mg/kg)-treated group, ZSCLE (200 mg/kg)-treated group, and ZSCLE (300 mg/kg)-treated group. Pretreatment with ZSCLE (100, 200, and 300 mg/kg) restored the normal heart rate (HR); decreased the elevated levels of malondialdehyde; the activity of myeloperoxidase, nitric oxide (NO), and inducible NO synthase; and the expression of nuclear factor kappa B (NF-κB), but increased the content of glutathione and antioxidant enzyme activities in mice with sepsis. Moreover, the results of biochemical analyses and qRT-PCR indicated that ZSCLE treatment lowered the level of cytokines, including tumor necrosis factor alpha and interleukin (IL)-1β. Additionally, ZSCLE reduced myocardial and renal apoptosis by inducing the downregulation of caspase-3 and Bax mRNA and upregulation of the expression of Bcl-2. Based on these results, we suggest that ZSCLE has a protective effect against multiple-organ impairment that follows sepsis. This effect may be attributed to the antioxidant, anti-inflammatory, and anti-apoptotic activities of ZSCLE.