With increasing demand for meat and dairy products, the volume of wastewater generated from the livestock industry has become a significant environmental concern. The treatment of livestock wastewater (LWW) is a challenging process that involves removing nutrients, organic matter, pathogens, and other pollutants from livestock manure and urine. In response to this challenge, researchers have developed and investigated different biological, physical, and chemical treatment technologies that perform better upon optimization. Optimization of LWW handling processes can help improve the efficacy and sustainability of treatment systems as well as minimize environmental impacts and associated costs. Response surface methodology (RSM) as an optimization approach can effectively optimize operational parameters that affect process performance. This review article summarizes the main steps of RSM, recent applications of RSM in LWW treatment, highlights the advantages and limitations of this technique, and provides recommendations for future research and practice, including its cost-effectiveness, accuracy, and ability to improve treatment efficiency.