Glaucoma is a group of progressive optic neuropathies characterized by the degeneration of retinal ganglion cells (RGCs) and their axons, leading to irreversible vision loss or blindness if left untreated. Current glaucoma treatments primarily focus on lowering intraocular pressure (IOP), the only proven method to slow disease progression. However, these treatments do not effectively address RGC loss or promote optic nerve regeneration. Emerging research into both natural and synthetic bioactive compounds offers promising new avenues for glaucoma management. This review explores the multifaceted therapeutic potential of bioactive compounds in glaucoma treatment, focusing on their mechanisms of action in IOP reduction and neuroprotection, as well as antioxidant and anti-inflammatory effects. We further review ongoing clinical trials and discuss significant challenges to clinical translation, including the issues of bioavailability, standardization, long-term safety, and regulatory challenges. Furthermore, this paper highlights the potential of integrating precision medicine into bioactive treatments, emphasizing the value of personalized care based on genetic and phenotypic profiles. Finally, the review discusses the role of combination therapies, which leverage the complementary mechanisms of bioactive compounds and conventional treatments. As research progresses, the development of targeted, bioactive-based therapies could transform glaucoma management, offering more comprehensive and effective options for patients with this vision-threatening disease.