Objective To observe the effects of plantar injection of complete Freund’s adjuvant (CFA)on paindepressive behavior and changes in hippocampal monoamine neurotransmitters in rats to establish an animal model of related comorbidity. Methods Sixteen male, 8-week-old, SPF-grade healthy SD rats were randomly divided into model and control groups with eight rats in each group. In the model group, rats were anesthetized and injected with 100 μL CFA in the left hind paw to induce the comorbid chronic inflammatory pain and depression model. In the control group, rats were injected with the same volume of saline. Pain thresholds were measured using the Von Frey hair and thermal radiation instrument, and depression-like behaviors were assessed using the open field test (OFT), tail suspension test (TST), and forced swim test ( FST). Enzyme-linked immunosorbent assays were used to measure 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE)in rat hippocampal tissue. Histological changes in the hippocampal area were observed by hematoxylin-eosin(HE) staining. Results Compared with the control group, the mechanical withdrawal threshold and thermal withdrawal latency in the model group were significantly decreased at 3, 7, and 14 days (P< 0. 01). The total distance in the OFT was significantly reduced at 7 and 14 days (P< 0. 01), and the time spent in the center zone was significantly decreased at 14 days (P< 0. 01). Immobility time in the TST was significantly increased at 14 days (P<0. 01), and the immobility time in the FST was significantly increased at 7 and 14 days(P< 0. 05, P< 0. 01). 5-HT, DA, and NE contents in hippocampal tissue of the model group rats were significantly reduced compared with those in the control group (P< 0. 01), and hippocampal tissue in the model group showed pathological changes, including irregular neuronal shapes, loose and disordered arrangement, increased intercellular space, some unclear cell nuclei, and some neuronal contraction and apoptosis. Conclusions Injection of 100 μL CFA into the footpad causes pain hypersensitivity, depression-like behavior, significant reductions in monoaminergic neurotransmitters in the hippocampus, and histological changes in the hippocampus, effectively simulating the manifestations of comorbid pain and depression, and is an experimental model to study the pathological mechanisms of comorbid chronic inflammatory pain and depression.