Pharmaceuticals and personal care products (PPCPs) from specific activities often enter surface and groundwater, adversely affecting the physiological functions of non-target organisms and posing a serious threat to a wide range of aquatic organisms. Therefore, the aim of this study was to investigate the effects of environmentally relevant concentrations of the antipsychotic drugs sulpiride and clozapine on dopaminergic (DAergic) and serotonergic (5-hydroxytryptaminergic, i.e., 5-HTergic) neurotransmitter systems in the brain of a short-arm octopus (Octopus ochellatus). Octopus ochellatus adults were exposed to environmentally relevant concentrations of sulpiride, clozapine, or a mixture of sulpiride and clozapine. The effects of the drug on the transcription and expression levels of major functional molecules in the DAergic and 5-HTergic systems of the brain were analyzed. By antagonizing the dopamine receptor D2 (DRD2) or 5-hydroxytryptamine receptor 2A (5-HTR2A), the two drugs induced abnormal transcription and expression levels of important functional molecules in the brain’s DA and 5-HT signaling pathways. In addition, dose-dependent adverse reactions were observed with these antipsychotics. Our results suggest that sulpiride and clozapine interfere with DAergic and 5-HTergic neurotransmitter systems in the brain of Amphioctopus fangsiao (O. ochellatus), possibly affecting brain functions, such as reproduction, predation, camouflage, learning, and memory. As a result, they pose a serious threat to the health of Amphioctopus fangsiao.