Octopus maya is a major socio-economic resource from the Yucatán Peninsula in Mexico. In this study we report for the first time the chemical composition of the saliva of O. maya and its effect on natural prey, i.e. the blue crab (Callinectes sapidus), the crown conch snail (Melongena corona bispinosa), as well as conspecifics. Salivary posterior glands were collected from octopus caught by local fishers and extracted with water; this extract paralyzed and predigested crabs when it was injected into the third pereiopod. The water extract was fractionated by membrane ultrafiltration with a molecular weight cut-off of 3 kDa leading to a metabolic phase (>3 kDa) and a neurotoxic fraction (<3 kDa). The neurotoxic fraction injected in the crabs caused paralysis and postural changes. Crabs recovered to their initial condition within two hours, which suggests that the effects of the neurotoxic fraction were reversible. The neurotoxic fraction was also active on O. maya conspecifics, partly paralyzing and sedating them; this suggests that octopus saliva might be used among conspecifics for defense and for reduction of competition. Bioguided separation of the neurotoxic fraction by chromatography led to a paralysis fraction and a relaxing fraction. The paralyzing activity of the saliva was exerted by amino acids, while the relaxing activity was due to the presence of serotonin. Prey-handling studies revealed that O. maya punctures the eye or arthrodial membrane when predating blue crabs and uses the radula to bore through crown conch shells; these differing strategies may help O. maya to reduce the time needed to handle its prey.