The prevalence of substandard and falsified medicines in low- and middle-income countries (LMICs) is a major global public health concern. Multiple screening technologies for post-market surveillance of medicine quality have been developed but there exists no clear guidance on which technology is optimal for LMICs. This study examined the return on investment (ROI) of implementing a select number of screening technologies for post-market surveillance of amoxicillin quality in a case study of Kenya. An agent-based model, Examining Screening Technologies using Economic Evaluations for Medicines (ESTEEM), was developed to estimate the costs, benefits, and ROI of implementing screening technologies for post-market surveillance of substandard and falsified amoxicillin for treatment of pediatric pneumonia in Kenya. The model simulated sampling, testing, and removal of substandard and falsified amoxicillin from the Kenyan market using five screening technologies: (1) Global Pharma Health Fund’s GPHF-Minilab, (2) high-performance liquid chromatography (HPLC), (3) near-infrared spectroscopy (NIR), (4) paper analytical devices / antibiotic paper analytical devices (PADs/aPADs), and (5) Raman spectroscopy. The study team analyzed the population impact of utilizing amoxicillin for the treatment of pneumonia in children under age five in Kenya. We found that the GPHF-Minilab, NIR, and PADs/aPADs were similar in their abilities to rapidly screen for and remove substandard and falsified amoxicillin from the Kenyan market resulting in a higher ROI compared to HPLC. NIR and PADs/aPADs yielded the highest ROI at $21 (90% Uncertainty Range (UR) $5-$51) each, followed by GPHF-Minilab ($16, 90%UR $4 - $38), Raman ($9, 90%UR $2 - $21), and HPLC ($3, 90%UR $0 - $7). This study highlights screening technologies that can be used to reduce costs, speed up the removal of poor-quality medicines, and consequently improve health and economic outcomes in LMICs. National medicine regulatory authorities should adopt these fast, reliable, and low-cost screening technologies to better detect substandard and falsified medicines, reserving HPLC for confirmatory tests.