Background and Purpose: Our previous studies have demonstrated that angiotensin II receptor type 1 (AT1R) in the brain could be a potential treatment for methamphetamine (METH)-induced dependence. The present study aimed to investigate the underlying mechanisms of the inhibitory effect of AT1R on various behavioural effects of METH. Experimental Approach: We first examined the effect of AT1R antagonist, candesartan cilexetil (CAN), on behavioural and neurotoxic effects of METH in vivo and in vitro. We subsequently examine the changes of AT1R and PLCβ1 in vivo and in vitro. Furthermore, we studied the role of PLCβ1 blockade on METH-induced neurotoxicity and synaptic plastic changes. We finally examined the effect of PLCβ1 blockade on the reinforcing and motivational effects of METH. Key Results: CAN significantly elevated METH-induced behavioral dysfunction and neurotoxicity associated with increased oxidative stress. AT1R and phospholipase C β1 (PLCβ1) were significantly upregulated in vivo and in vitro. Inhibition of PLCβ1, effectively alleviated METH-induced neurotoxicity and METH self-administration (SA) by central blockade of the PLCβ1-protein kinase C alpha (PKCα)-cAMP response element-binding protein (CREB) signalling pathway. PLCβ1 blockade significantly decreased the reinforcing and motivation effects of METH. Conclusion and Implications: PLCβ1-PKCα-CREB signalling pathway, as well as a more specific role of PLCβ1, involved the inhibitory effects of CAN on METH-induced behavioural dysfunction and neurotoxicity. Our findings reveal a novel role of PLCβ1 in METH-induced neurotoxicity and METH use disorder.