Neuroinflammation is a key factor in the onset and advancement of several neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. The continuous activation of microglia and astrocytes, coupled with the release of proinflammatory cytokines as well as reactive oxygen and nitrogen species, leads to neuronal dysfunction and loss. The constraints of existing therapies for central nervous system inflammation require the investigation of innovative approaches. Photochemical interventions, encompassing natural photoactive phytochemicals and light-based therapies, signify promising alternatives to traditional treatments. Recent breakthroughs in photomedicine have identified numerous photoactive natural chemicals with neuroprotective properties, predominantly sourced from plants. This chapter investigates the molecular mechanisms through which neuroinflammation influences neurodegenerative pathology and analyzes novel photo compounds that may regulate critical inflammatory signaling pathways, including NF-κB, NLRP3 inflammasome, and MAPK cascades. Recent studies primarily focus on curcumin, resveratrol, hypericin, and other light-activated phytochemicals that exhibit immunomodulatory and antioxidant activities. The focus is on the role of light-assisted delivery systems and photobiomodulation in improving the bioavailability and therapeutic efficacy of these molecules. Additionally, it examines the potential and challenges associated with the development of phototherapeutic strategies for neuroinflammation and the management of chronic neurodegenerative diseases, incorporating recent findings.