Zilla spinosa is commonly used in traditional medicine to treat gastrointestinal disorders and diabetes. In this study, aqueous ethanol (AE) and aqueous methanol (AM) extracts from aerial parts and roots of Z. spinosa were investigated. The total phenolic (TPC) and flavonoid (TFC) contents and antioxidant capacities in terms of 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging, hydrogen peroxide (H2O2), and ferric reducing antioxidant power (FRAP) assays were determined, and the correlations among the results were assessed using Pearson’s correlation. The antimicrobial activity was assessed through agar disc diffusion and broth microdilution assays. Phytochemical screening showed that Z. spinosa extracts had alkaloids, glycosides, saponins, triterpenoids, phenols, and flavonoids in different abundances. The aerial part-AE extract contained low TPC (30.17 ± 4.24 mg GAE/g) and TFC (7.40 ± 1.02 mg QE/g) and displayed significant antioxidant capacity in the DPPH (IC50 = 52.17 ± 7.30 μg/mL), H2O2 (91.22 ± 2.60 μg/mL), and FRAP (EC50 = 98.70 ± 2.21 μg/mL) assays. By contrast, the root-AM extract contained high amounts of TPC (87.72 ± 7.75 mg GAE/g) and TFC (25.60 ± 1.57 mg QE/g). It showed significantly high antioxidant activity with IC50 values of 12.33 ± 1.88 μg/mL in the DPPH and 39.37 ± 2.59 μg/mL in the H2O2 assays, as well as reducing power capacity with an EC50 value of 20.82 ± 1.14 μg/mL in the FRAP assay. Both TPC and TFC were exhibited negative correlations (
p
<
0.01
) with the IC50 and EC50 values obtained in the applied antioxidant assays. The aerial part-AM extract showed the highest inhibitory activity against Staphylococcus aureus (26.5 ± 0.20 mm), followed by Shigella flexneri (19.4 ± 0.40 mm) and Proteus mirabilis (17.7 ± 0.49 mm). S. aureus was the most affected microorganism with a minimum inhibitory concentration of 128 μg/mL against the aerial part-AM extract. Interestingly, all evaluated extracts showed potent antifungal activity against Candida albicans. However, aerial part-AM was the most effective, with an inhibition zone of 12.6 ± 0.17 mm. The results concluded that Z. spinosa possesses different phytochemicals displaying significant antioxidant and antimicrobial activities, thus lending credence to its use in traditional medicine.