Objective To observe the effects of plantar injection of complete Freund's adjuvant (CFA) on pain-depressive behavior and changes in hippocampal monoamine neurotransmitters in rats, with the aim of establishing an animal model of related comorbidity. Methods 16 male, 8-week-old, SPF-grade healthy SD rats were randomly divided into a model group and control group with 8 rats in each group. In the model group, rats were anesthetized and injected with 100 μL of CFA in the left hind paw to induce the comorbid 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 depressive-like behaviors were assessed using open field test (OFT), tail suspension test (TST), and forced swim test (FST). Enzyme-linked immunosorbent assay (ELISA) was used to measure the content of 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) in the rat hippocampal tissue, and histological changes in the hippocampal area were observed by hematoxylin-eosin (HE) staining. Results Compared with the control group, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) 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); the 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); the content of 5-HT, DA, and NE in the hippocampal tissue of the model group rats was significantly reduced compared with the control group (P < 0.01), and the 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. Conclusion Injection of 100 μL of CFA in the footpad can cause pain hypersensitivity, depressive-like behavior, significant reduction of 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 for studying the pathological mechanisms of comorbid pain and depression.