AbstractCombinations of different biomaterials with their own advantages as well as functionalization with other components have long been implemented in tissue engineering to improve the performance of the overall material. Biomaterials, particularly hydrogel platforms, have shown great potential for delivering compounds such as drugs, growth factors, and neurotrophic factors, as well as cells, in neural tissue engineering applications. In central the nervous system, astrocyte reactivity and glial scar formation are significant and complex challenges to tackle for neural and functional recovery. GelMA hydrogel‐based tissue constructs have been developed in this study and combined with two different formulations of phosphate glass fibers (PGFs) (with Fe³⁺ or Ti²⁺ oxide) to impose physical and mechanical cues for modulating astrocyte cell behavior. This study was also aimed at investigating the effects of lithium‐loaded GelMA‐PGFs hydrogels in alleviating astrocyte reactivity and glial scar formation offering novel perspectives for neural tissue engineering applications. The rationale behind introducing lithium is driven by its long‐proven therapeutic benefits in mental disorders, and neuroprotective and pronounced anti‐inflammatory properties. The optimal concentrations of lithium and LPS were determined in vitro on primary rat astrocytes. Furthermore, qPCR was conducted for gene expression analysis of GFAP and IL‐6 markers on primary astrocytes cultured 3D into GelMA and GelMA‐PGFs hydrogels with and without lithium and in vitro stimulated with LPS for astrocyte reactivity. The results suggest that the combination of bioactive phosphate‐based glass fibers and lithium loading into GelMA structures may impact GFAP expression and early IL‐6 expression. Furthermore, GelMA‐PGFs (Fe) constructs have shown improved performance in modulating glial scarring over GFAP regulation.