The present study is based on optimized green synthesis of silver nanoparticles (AgNPs) using Manilkara zapota fruit extract, formulation of topical gels, and evaluation for their antimicrobial properties. The results reveal that a reaction temperature of 35 °C and a reaction time of 11 h are the optimum conditions to get spherical AgNPs with a particle size of 100.7 nm and a zeta potential of −26.7 mV. The synthesized AgNPs formulated as topical gels demonstrate a broad-spectrum antimicrobial activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Aspergillus niger in comparison to the 0.2% (mass fraction) silver nitrate marketed formulation. The AgNPs loaded gels seem promising and could lead to a useful alternative for treating pathogenic infections.