Nicotinic acetylcholine receptors (nAChRs) are critical ligand-gated ion channels in the human nervous system. They are targets for various neurotoxins produced by algae, plants, and animals. While there have been many structures of nAChRs bound by neurotoxins published, the binding mechanism of toxins to the nAChRs remains uncleared. In this work, we have performed extensive Gaussian accelerated molecular dynamics simulations on severalAplysia californica(AC) nAChRs in complex with α-conotoxins, strychnine, and pinnatoxins, as well as human nAChRs in complex with α-bungarotoxin and α-conotoxin for a total of 60 μs of simulation time to determine the binding and dissociation pathways of the toxins to the nAChRs and the associated effects. We uncovered two common binding and dissociation pathways shared by toxins and nAChRs. In the primary binding pathway, the toxins diffused from the bulk solvent to first bind a region near the extracellular pore before moving downwards along the nAChRs to the nAChR orthosteric pocket. The second binding pathway involved a direct diffusion of the toxins from the bulk solvent into the nAChR orthosteric pocket. The dissociation pathways were the reverse of the observed binding pathways. We also found that the toxins enacted their toxicity upon binding by restricting the necessary movements required by the nAChRs to open their extracellular and intracellular pores for the ions to pass through. Notably, the electrostatically bipolar interactions between nAChR orthosteric pocket and toxins provides a molecular level explanation for the common binding mode shared by diverse toxins and serve as a key determinant for toxicity.