Lead (Pb) is well known for the containment of soil surfaces. In the last few decades, phytoremediation has been the most ideal technology to extract Pb from soil, involving numerous chemical reactions and cost analysis. The aim of this study is to model and to optimize Pb extraction from the contaminated soil via Pelargonium hortorum by comparing two modeling approaches: response surface methodology (RSM) and artificial neural networks (ANNs) with the genetic algorithm (GA). To determine the significance of the proposed solution, in vitro essays were performed to check the Pb tolerance of bacterial strains (NCCP 1844, 1848, 1857, and 1862), followed by the co-application of bacteria and citric acid on a Pb hyperaccumulator (Pelargonium hortorum L.) on Murashige and Skoog (MS) agar medium. Afterwards, a pot culture experiment was performed to optimize Pb extraction competency from Pb-spiked (0 mg kg−1, 500 mg kg−1, 1000 mg kg−1, and 1500 mg kg−1) soil by Pelargonium hortorum L., to which citric acid (5 and 10 mmol L−1) and Microbacterium paraoxydance (1 and 1.5 OD) were applied. Plants were harvested at 30, 60, and 90 day intervals, and they were analyzed for dry biomass and Pb uptake characteristics. The maximum Pb extraction efficiency of 86.0% was achieved with 500 mg kg−1 soil Pb for 60 days. Furthermore, RSM, based on the Box–Behnken design (BBD) and the ANN-based Levenberg–Marquardt Algorithm (LMA), were applied to model Pb extraction from the soil. The significance of the predicted values from RSM and LMA were close to 36.0% and 86.05%, respectively, compared to the laboratory values. The comprehensive evaluation of these findings encouraged the accuracy, reliability, and efficiency of the ANN for the optimization process. Therefore, experimental results showed that ANN is an accurate technique to optimize an integrated phytoremediation system for sustainable Pb removal, besides being environmentally friendly and potentially cost-effective.