Tryptophan (Trp) metabolism plays a central role in neuroimmune communication, integrating immune, metabolic, endocrine, and neural responses. In addition to serving as a precursor for serotonin and melatonin biosynthesis, Trp is metabolized by both host cells and the gut microbiota, generating bioactive metabolites that influence gut homeostasis, immune regulation, and brain function. Approximately 95% of free Trp is metabolized via the kynurenine pathway through indoleamine 2,3-dioxygenase-1 (IDO-1) and tryptophan 2,3-dioxygenase (TDO), a pathway considered inflammatory, producing neuroactive metabolites such as kynurenine (KYN), quinolinic acid (QUIN), kynurenic acid (KYNA), and 3-hydroxykynurenine (3-HK). In parallel, a portion of intestinal tryptophan is converted by the gut microbiota into indole and indole-derived metabolites, including indole-3-acetic acid (IAA), indole-3-propionic acid (IPA), and indole-3-aldehyde (IAld). These microbial metabolites contribute to intestinal barrier integrity, immune homeostasis, and gut-brain axis signaling, primarily through activation of the aryl hydrocarbon receptor (AhR). Growing evidence indicates that inflammatory signals mediated by Toll-like receptors (TLRs), interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β) induce IDO-1 activity, redirecting tryptophan metabolism to the kynurenine pathway and promoting the accumulation of neurotoxic metabolites at the expense of neuroprotective indole-derived compounds. Furthermore, environmental factors such as heavy metals, pesticides, air pollutants, and microplastics can trigger gut dysbiosis and neuroinflammation, thus disrupting tryptophan metabolism and gut-brain communication. This review discusses the mechanisms by which TLR activation, environmental toxins, gut dysbiosis, and dysregulation of the kynurenine and indole pathways contribute to neuroinflammation and neurodegeneration. Additionally, we highlight emerging therapeutic targets, including IDO-1 inhibitors and modulation of kynurenine monooxygenase (KMO), sensitization of AhR, GPR35, and microbiota-derived metabolites, as promising strategies for the prevention and treatment of neurodegenerative disorders.