Endocannabinoid system is considered a relevant player in the regulation of neuronal excitability, since it contributes to maintaining the balance of the synaptic ionic milieu. Perturbations to bioelectric conductances have been implicated in the pathophysiological processes leading to hyperexcitability and epileptic seizures. Cannabinoid influence on neurosignalling is exerted on classic receptor-mediated mechanisms or on further molecular targets. Among these, transient receptor potential vanilloid (TRPV) are ionic channels modulated by cannabinoids that are involved in the transduction of a plethora of stimuli and trigger fundamental downstream pathways in the post-synaptic site. In this review, we aim at providing a brief summary of the most recent data about the cross-talk between cannabinoid system and TRPV channels, drawing attention on their role on neuronal hyperexcitability. Then, we aim to unveil a plausible point of interaction between these neural signalling systems taking into consideration nitric oxide, a gaseous molecule inducing profound modifications to neural performances. From this novel perspective, we struggle to propose innovative cellular mechanisms in the regulation of hyperexcitability phenomena, with the goal of exploring plausible CB-related mechanisms underpinning epileptic seizures.