Chemotherapy-induced peripheral neuropathy (CIPN) is a one of side effect in cancer patients that receive antineoplastic agent, like oxaliplatin. Orexinergic system in the hypothalamus is the one of system that modulate nociceptive and neuropathy. Because there is flavonoids such as resveratrol and andrographolide that may prevent chemotherapy induced peripheral neuropathy, this study analyzed effects of andrographolide and resveratrol treatment on PPOrx and OX1R mRNA expression in hypothalamic oxaliplatin-induced mice. Materials and Methods This study was conducted for 22 days in mice. Mice injected with oxaliplatin followed by andrographolide or resveratrol. Chemotherapy induced peripheral neuropathic pain was assessed based on withdrawal threshold, mRNA PPOrx expression, and mRNA OX1R expression. Results The results showed that intraperitoneal injection of 100mg/kg resveratrol and 20mg/kg andrographolide increased the withdrawal threshold after oxaliplatin induction. Resveratrol administration also increased the relative expression of PPOrx mRNA significantly, but not the OX1R mRNA relative expression. On the other hand, administration of andrographolide did not cause a change in the expression of PPOrx and OX1R in the hypothalamus. Conclusions Intraperitoneal injection of andrographolide and resveratrol reduces the mechanical allodynia response in oxaliplatin-induced mice significantly. The mechanism of andrographolide increases the withdrawal threshold does not via the orexinergic system, but the mechanism of resveratrol via the orexinergic system.