Sulfamethoxazole (SUX) is a common pharmaceutical, but represents a potential global threat to human health due to its exhaustive use and consequent outflow in the environment. This situation calls for development of a cost-effective approach to remove SUX present in contaminated released from various sources. In this study, we developed green nanoemulsions to remove SUX from contaminated water samples. Parameters predicted by Hansen solubility (HSPiP software) were used to select excipients. Several trial batches (SN1–SN12) of green nanoemulsions were developed and characterized for size, zeta potential, polydispersity (PDI), and removal efficiency (%RE) to determine the input parameters (factors, levels, and responses) for an experimental design tool (Design-Expert) to identify the most critical variables controlling %RE and to optimize the nanoemulsion composition under set constraints. Transmission electron microscopy (TEM) confirmed the morphological behavior after 30 min of dispersion. Finally, the inductively coupled plasma-optical emission spectroscopy (ICP-OES) technique was used to confirm the absence of SUX in water treated with the optimized nanoemulsion. Results showed that SUX and eugenol closely interact based on Hansen solubility parameters and the experimental solubility data corroborated the predicted outcomes. Pseudo ternary-phase diagrams suggested various ratios of surfactant to co-surfactant (Smix) based on SN1–SN12 and that SN10 was the most suitable nanoemulsion for input parameters (Smix of 1:3, desired size 78 nm, lowest PDI 0.118, highest %RE 78%, and highest zeta potential +23 mV) in the experimental design program. In addition, Design-Expert identified the prime factors responsible to control %RE. OSEN1 was the most robust and optimized nanoemulsion with high overall desirability (0.94). Composition, globular size, viscosity, and contact time emerged as prime critical variables with a significant impact on the %RE of SUX from contaminated water using the green nanoemulsion. ICP-OES confirmed the absence of SUX from treated water. Overall, our results demonstrate that green nanoemulsions represent a promising and cost-effective approach to remove SUX from environmental water samples and alleviate safety concerns.