The combination of nanoemulgel and phytochemistry has resulted in several recent discoveries in the field of topical delivery systems. The present study aimed to prepare nanoemulgel based on turmeric (Curcuma longa) and neem (Azadirachta indica) against microbial infection as topical drug delivery. Olive oil (oil phase), Tween 80 (surfactant), and PEG600 (co-surfactant) were used for the preparation of nanoemulsion. Carbopol 934 was used as a gelling agent to convert the nanoemulsion to nanoemulgel and promote the control of the release of biological properties of turmeric and neem. The nanoemulsion was characterized based on particle size distribution, PDI values, and compatibility using FTIR analysis. In contrast, the nanoemulgel was evaluated based on pH, viscosity, spreadability, plant extract and excipient compatibility or physical state, in vitro study, ex vivo mucoadhesive study, antimicrobial properties, and stability. The resulting nanoemulsion was homogeneous and stable during the centrifugation process, with the smallest droplets and low PDI values. FTIR analysis also confirmed good compatibility and absence of phase separation between the oil substance, surfactant, and co-surfactant with both plant extracts. The improved nanoemulgel also demonstrated a smooth texture, good consistency, good pH, desired viscosity, ex vivo mucoadhesive strength with the highest spreadability, and 18 h in vitro drug release. Additionally, it exhibited better antimicrobial properties against different microbial strains. Stability studies also revealed that the product had good rheological properties and physicochemical state for a period of over 3 months. The present study affirmed that turmeric- and neem-based nanoemulgel is a promising alternative for microbial infection particularly associated with microorganisms via topical application.