Parkinson's disease (PD) and Alzheimer's disease (AD) are neurodegenerative disorders characterized by the interaction of genetic, environmental, and familial factors. The immune system, particularly microglia, plays a crucial role in these diseases, contributing to neuronal loss and symptom exacerbation. Researchers use various in vitro and in vivo models to understand the physiological and biological aspects of these diseases. Recent advancements in 3D models and organ-on-a-chip systems have improved the accuracy of disease modeling, offering potential for long-term disease-based therapeutic testing and reducing reliance on animal models. These models aim to aid in the development of effective treatments for PD and AD by providing a more realistic representation of the complex interactions within the neuroimmune system. The review highlights the significance of understanding the pathophysiology and biology of AD and PD, emphasizing the role of the immune system in disease progression. It also discusses the current treatments and clinical trials for these diseases, focusing on drug targets and immunomodulatory therapies. The article concludes by detailing the advantages and disadvantages of in vitro and in vivo models, with a focus on the potential of 3D models and organ-on-a-chip systems in advancing the field of neurodegenerative disease research.Parkinson's disease (PD) and Alzheimer's disease (AD) are neurodegenerative disorders characterized by the interaction of genetic, environmental, and familial factors. The immune system, particularly microglia, plays a crucial role in these diseases, contributing to neuronal loss and symptom exacerbation. Researchers use various in vitro and in vivo models to understand the physiological and biological aspects of these diseases. Recent advancements in 3D models and organ-on-a-chip systems have improved the accuracy of disease modeling, offering potential for long-term disease-based therapeutic testing and reducing reliance on animal models. These models aim to aid in the development of effective treatments for PD and AD by providing a more realistic representation of the complex interactions within the neuroimmune system. The review highlights the significance of understanding the pathophysiology and biology of AD and PD, emphasizing the role of the immune system in disease progression. It also discusses the current treatments and clinical trials for these diseases, focusing on drug targets and immunomodulatory therapies. The article concludes by detailing the advantages and disadvantages of in vitro and in vivo models, with a focus on the potential of 3D models and organ-on-a-chip systems in advancing the field of neurodegenerative disease research.