Studying the human brain, the most complex organ of the body, remains a challenge in the research field until today. The pioneering development of in vitro models that represent with high fidelity the intricate environment of the brain has been crucial for the better understanding of the central nervous system physiology and pathology, as well as for the discovery of new targets and drugs to tackle neurological disorders. In this context, three-dimensional (3D) cell culture systems have emerged as a valuable tool for the development of more physiologically relevant brain models that allow for the study of cell–cell interactions, extracellular matrix (ECM) influences, and the role of biophysical cues in brain development and function. Astrocytes are glial cells with essential roles in brain homeostasis and disease. However, their complex interactions with other cell types and the extracellular matrix (ECM), and their contribution in healthy and pathological conditions are not fully understood. Incorporating astrocytes into 3D culture models provides a promising avenue for elucidating their functions and exploring their potential as therapeutic targets. Here, we overview the unique characteristics of the brain’s ECM and dive into different tissue engineering approaches established for the 3D cell culture of astrocytes. We describe advances in the field of biomaterials and list the main tissue engineered models that investigate the astrocyte phenotype and function. Furthermore, we highlight the mechanical properties as an important element to be included in future advanced models. While the field of glial tissue engineering still faces some challenges ahead, combining neuroscience, bioengineering, and mechanobiology holds great promise for developing groundbreaking models that will revolutionize brain research and brain disorders management.