The 5-hydroxytryptamine (5-HT) receptor is significant for the regulation of mood and memory. However, the role of 5-HTR in β-Amyloid protein (Aβ)-induced cognitive decline, neuroinflammation and the possible mechanism remains elusive. Thus, we aimed to evaluate the effects of 5-HTR on Aβ-induced learning and memory decline and neuroinflammation in mice. Novel object recognition and Morris water maze tests were performed to observe learning and memory behavior in mice. Protein levels of Iba1, GFAP, MAP2, TNF-α, Tβ4, C-fos, IKK-β, IKB-α, NF-κBp65, phospho-NF-κBp65 in the hippocampus were examined by immunostaining or western blotting. Aβ-treatment inducing learning and memory decline was shown in novel object recognition and Morris water maze tests; neuroinflammation shown in immunostaining. Our study found out that 5-HTR inhibitor WAY100635 showed significant improvement in Aβ-induced learning and memory decline. Moreover, WAY100635 decreases levels of Iba1, GFAP, and TNF-α in the hippocampus, which were related to neuroinflammation. While treatment with 5-HTR agonist 8-OH-DPAT or ERK inhibitor U0126 exerted no effects or even aggravated Aβ-induced learning and memory decline. In addition, WAY100635 could downregulate phospho-NF-κB in the hippocampus of Aβ-injected mice. These results provide new insight into the mechanism, for 5-HTR in Aβ-induced cognitive impairments through crosstalk with the NF-κB signaling pathway. Our data indicated that WAY100635 was involved in the protective effects against neuroinflammation and improvement of learning and memory in Alzheimer's disease.