Alzheimer’s disease (AD) has become an important public health issue worldwide. p-Coumaric acid (CA) and lactoferrin (Lf) possessed antioxidant, anti-inflammatory, and anti-AD activities. Herein, we hypothesized that a combination treatment of CA and Lf would synergistically improve AD symptoms and studied its mechanisms. Twelve-week-old amyloid precursor protein (APP)/presenilin 1 (PS1) mice were treated with CA, Lf, or both CA and Lf for 8 weeks. Results showed that individual and combined treatments could ameliorate cognitive deficits to varying degrees, with stronger effects for combined intervention than for CA or Lf alone. Specifically, combined treatment was most effective in improving nesting ability and reducing amyloid β1−42 (Aβ1−42) deposition in mice. Moreover, combined treatment was more effective in suppressing APP, β-site APP cleavage enzyme 1, and inflammation; it inhibited the CCAAT-enhancer-binding protein (C/EBPβ)/asparagine endopeptidase (AEP) signaling pathway in the hippocampus and colon and upregulated the expression of tight junction protein zonula occludens-1 in the colon; it also decreased the Firmicutes/Bacteroidetes ratio at the phylum level and increased the relative abundance of Prevotellaceae, Lachnospira, and Eubacterium at the genus level. Overall, the combination of CA and Lf may ameliorate cognitive deficits in APP/PS1 mice by improving inflammation and inhibiting the C/EBPβ/AEP signaling pathway via modulating gut microbiome.