Antimicrobial resistance is one of the crucial public health challenges that we need to combat. Thus, in concern over public health and the economy, controlling the emergence of infectious diseases is critical worldwide. One of the ways to overcome the influences of antimicrobial resistance is by developing new, efficient, and improved antimicrobial agents. Medicinal plant-derived silver nanoparticles (AgNPs) are under intensive examination for a variety of therapeutic purposes and targeted applications in nanomedicine and nanotechnology. Plants belonging to the genus Thevetia [Syn. Casabela], which is known for its medicinal uses and has rarely been applied for the synthesis of AgNPs, is an attractive alternative as they have a high content of secondary metabolites. Herein, using aqueous leaf extract of Cascabela thevetia, which was locally found in the Makkah region, Saudi Arabia, green synthesis of AgNPs is reported. Active components of Cascabela thevetia aqueous leaf extract were sufficient to reduce AgNO3 into AgNPs and stabilize them as this was confirmed through UV-Visible absorption, Fourier transforms infrared (FTIR), X-ray diffraction (XRD), filed emission scanning electron microscopy (FESEM), and transmission electron microscopy (TEM) studies. UV-Visible, HPLC, and FTIR analysis demonstrated the presence of gallic acid in aqueous extract and solution of C-AgNPs. The spherical Cascabela thevetia derived C-AgNPs with an average diameter in the range of 20−30 nm were highly dispersed, as seen from FESEM and TEM images, and demonstrated the high antibacterial and antifungal activities when incubated with Gram-positive bacteria Methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus (S. aureus), Enterococcus faecalis (E. faecalis), Gram-negative bacteria Escherichia coli (E. coli), Salmonella typhimurium (S. typhimurium), Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa) and fungi Candida albicans (C. albicans) and Candida parapsilosis (C. parapsilosis). The lowest MIC values of C-AgNPs versus S. aureus, E. faecalis, and E. coli were found. Finally, the antioxidant activity and catalytic property of C-AgNPs were assessed by neutralizing DPPH free radical and reducing methylene blue and rhodamine B dyes, respectively.