This review summarizes the development of indole-based compounds as potential anti-neurodegenerative agents. Neurodegenerative diseases (NDs) are complex conditions involving multiple factors and mechanisms, including protein aggregation, oxidative stress, mitochondrial dysfunction, and inflammation. Despite significant research efforts, effective treatments remain elusive. Indole-based compounds, due to their versatile pharmacophore properties and ability to interact with various molecular targets, have attracted attention for their potential in modulating these pathological processes. Cholinesterase (ChE) inhibitors, such as donepezil, rivastigmine, and galantamine, are widely used in Alzheimer's disease (AD) treatment. Recent studies have focused on developing novel indole-based ChE inhibitors with improved potency and selectivity. For example, compound 1, a dual-binding inhibitor, showed high activity against both human AChE and BChE. Similarly, compounds 2–10, derived from tryptophan, demonstrated potent BChE inhibition, with compound 10 showing an IC50 of 56.9 nM. Indole-based sulfonamide derivatives also showed promising BChE inhibitory activity, with compound 11a exhibiting IC50 values of 0.10 μM for AChE and 0.20 μM for BChE. Protein aggregation inhibitors, such as Ro-31-8220, have shown potential in mitigating tau-induced neurotoxicity in AD. These compounds reduce phosphorylated tau levels and improve cognitive and motor functions in animal models. Additionally, indole-based hydrazide-hydrazone derivatives, such as 12a and 12b, demonstrated strong inhibitory activity against AChE and BChE, with compound 12a showing an IC50 of 4.33 μM for BChE. MAO-B inhibitors, such as selegiline and rasagiline, are used in Parkinson's disease (PD) treatment. Recent studies have identified indole analogs, such as 14a and 14b, as selective MAO-B inhibitors with low micromolar concentrations. These compounds showed favorable BBB permeation and low cytotoxicity. Adenosine A2A receptor antagonists, such as compounds 15 and 16, have shown potential in PD treatment by modulating dopaminergic neurotransmission. These compounds demonstrated affinity for both A2AAR and D2R, with compound 16 showing agonistic activity for D2R. PERK signaling inhibitors, such as compound 18, have shown neuroprotective effects in PD by reducing ER stress and neuronal dysfunction. AMPK activators, such as compound 21, have demonstrated potential in improving energy metabolism and neuroprotection in various NDs. 5-HT6 receptor antagonists, such as compound 22This review summarizes the development of indole-based compounds as potential anti-neurodegenerative agents. Neurodegenerative diseases (NDs) are complex conditions involving multiple factors and mechanisms, including protein aggregation, oxidative stress, mitochondrial dysfunction, and inflammation. Despite significant research efforts, effective treatments remain elusive. Indole-based compounds, due to their versatile pharmacophore properties and ability to interact with various molecular targets, have attracted attention for their potential in modulating these pathological processes. Cholinesterase (ChE) inhibitors, such as donepezil, rivastigmine, and galantamine, are widely used in Alzheimer's disease (AD) treatment. Recent studies have focused on developing novel indole-based ChE inhibitors with improved potency and selectivity. For example, compound 1, a dual-binding inhibitor, showed high activity against both human AChE and BChE. Similarly, compounds 2–10, derived from tryptophan, demonstrated potent BChE inhibition, with compound 10 showing an IC50 of 56.9 nM. Indole-based sulfonamide derivatives also showed promising BChE inhibitory activity, with compound 11a exhibiting IC50 values of 0.10 μM for AChE and 0.20 μM for BChE. Protein aggregation inhibitors, such as Ro-31-8220, have shown potential in mitigating tau-induced neurotoxicity in AD. These compounds reduce phosphorylated tau levels and improve cognitive and motor functions in animal models. Additionally, indole-based hydrazide-hydrazone derivatives, such as 12a and 12b, demonstrated strong inhibitory activity against AChE and BChE, with compound 12a showing an IC50 of 4.33 μM for BChE. MAO-B inhibitors, such as selegiline and rasagiline, are used in Parkinson's disease (PD) treatment. Recent studies have identified indole analogs, such as 14a and 14b, as selective MAO-B inhibitors with low micromolar concentrations. These compounds showed favorable BBB permeation and low cytotoxicity. Adenosine A2A receptor antagonists, such as compounds 15 and 16, have shown potential in PD treatment by modulating dopaminergic neurotransmission. These compounds demonstrated affinity for both A2AAR and D2R, with compound 16 showing agonistic activity for D2R. PERK signaling inhibitors, such as compound 18, have shown neuroprotective effects in PD by reducing ER stress and neuronal dysfunction. AMPK activators, such as compound 21, have demonstrated potential in improving energy metabolism and neuroprotection in various NDs. 5-HT6 receptor antagonists, such as compound 22