This review focuses on the development of indole-based compounds as potential anti-neurodegenerative agents, highlighting recent advances from 2018 to 2023. Neurodegenerative diseases (NDs) are characterized by the gradual loss of neurons in the central and peripheral nervous systems, leading to cognitive and motor impairments. Despite significant efforts in medicinal chemistry, effective treatments for NDs remain elusive. Indole, a naturally occurring heterocyclic compound, has emerged as a privileged scaffold due to its versatile pharmacophore properties and potential to modulate various molecular targets involved in NDs. The review covers several classes of indole-based compounds, including cholinesterase (ChE) inhibitors, protein aggregation inhibitors, monoamine oxidase B (MAO-B) inhibitors, adenosine A2A receptor antagonists, PERK signaling inhibitors, AMPK activators, and 5-HT6 receptor antagonists. Each section details the rational design strategies, structural-activity relationships (SARs), and biological activities of these compounds. For example, ChE inhibitors like tryptophanamide and their derivatives have shown promise in reducing cholinergic deficits in AD models. Protein aggregation inhibitors, such as Ro 31-8220, have demonstrated neuroprotective effects by reducing tau phosphorylation and improving memory in models of frontotemporal dementia. MAO-B inhibitors, including selegiline and rasagiline, have been explored for their potential in treating PD and AD. Adenosine A2A receptor antagonists, like idalopirdine, have shown cognitive enhancing effects in preclinical and clinical studies. PERK inhibitors, such as GSK2606414, have been effective in suppressing ER stress and protecting dopaminergic neurons in PD models. AMPK activators, including compound 21, have exhibited neuroprotective effects in HD models. 5-HT6 receptor antagonists, such as idalopirdine, have shown cognitive benefits in AD and PD models. Additionally, the review discusses multifunctional indole-based compounds that act as multitarget-directed ligands (MTDLs), combining multiple therapeutic activities. Examples include fascaplysin derivatives, cryptolepine, reserpine, ajmalicine, and azepino indoles, which have shown promise in inhibiting ChEs, preventing Aβ aggregation, and protecting neurons. Overall, the review underscores the potential of indole-based compounds in addressing the complex pathomechanisms of NDs, providing a comprehensive overview of recent advancements and future directions in the development of effective therapies.This review focuses on the development of indole-based compounds as potential anti-neurodegenerative agents, highlighting recent advances from 2018 to 2023. Neurodegenerative diseases (NDs) are characterized by the gradual loss of neurons in the central and peripheral nervous systems, leading to cognitive and motor impairments. Despite significant efforts in medicinal chemistry, effective treatments for NDs remain elusive. Indole, a naturally occurring heterocyclic compound, has emerged as a privileged scaffold due to its versatile pharmacophore properties and potential to modulate various molecular targets involved in NDs. The review covers several classes of indole-based compounds, including cholinesterase (ChE) inhibitors, protein aggregation inhibitors, monoamine oxidase B (MAO-B) inhibitors, adenosine A2A receptor antagonists, PERK signaling inhibitors, AMPK activators, and 5-HT6 receptor antagonists. Each section details the rational design strategies, structural-activity relationships (SARs), and biological activities of these compounds. For example, ChE inhibitors like tryptophanamide and their derivatives have shown promise in reducing cholinergic deficits in AD models. Protein aggregation inhibitors, such as Ro 31-8220, have demonstrated neuroprotective effects by reducing tau phosphorylation and improving memory in models of frontotemporal dementia. MAO-B inhibitors, including selegiline and rasagiline, have been explored for their potential in treating PD and AD. Adenosine A2A receptor antagonists, like idalopirdine, have shown cognitive enhancing effects in preclinical and clinical studies. PERK inhibitors, such as GSK2606414, have been effective in suppressing ER stress and protecting dopaminergic neurons in PD models. AMPK activators, including compound 21, have exhibited neuroprotective effects in HD models. 5-HT6 receptor antagonists, such as idalopirdine, have shown cognitive benefits in AD and PD models. Additionally, the review discusses multifunctional indole-based compounds that act as multitarget-directed ligands (MTDLs), combining multiple therapeutic activities. Examples include fascaplysin derivatives, cryptolepine, reserpine, ajmalicine, and azepino indoles, which have shown promise in inhibiting ChEs, preventing Aβ aggregation, and protecting neurons. Overall, the review underscores the potential of indole-based compounds in addressing the complex pathomechanisms of NDs, providing a comprehensive overview of recent advancements and future directions in the development of effective therapies.