Clostridium perfringens (C. perfringens) is one of the main pathogens which can cause a range of histotoxic and enteric diseases in humans or animals (pigs, or broilers). The Centers for Disease Control and Prevention (CDC) estimates these bacteria cause nearly 1 million illnesses in the United States every year. For animal husbandry, necrotizing enteritis caused by C. perfringens can cost the global livestock industry between $2 billion and $6 billion per year. C. perfringens-infected animals can be isolated for its identification and pathology. A suitable animal model is one of the essential conditions for studying the disease pathogenesis. In previous studies, mice have been used as subjects for a variety of Clostridium perfringens toxicity tests. Thus, this study was designed to build a mouse model infected porcine C. perfringens which was isolated from the C.perfringens-infected pigs. A total of 32 6-week-old male C57BL/6 mice were randomly divided into four groups. Control group was orally administrated with PBS (200 μL) on day 0. Low group, Medium group, and High group were gavaged with 200 ul of PBS resuspension containing 8.0 × 107 CFU, 4.0 × 108 CFU, and 2.0 × 109 CFU, respectively. We examined growth performance, immune status, intestinal barrier integrity, apoptosis-related genes expression, and copies of C. perfringens in mice. The results showed that the growth performance declined and intestinal structure was seriously damaged in High group. Meanwhile, pro-inflammatory factors (IL-1β, TNF-α, and IL-6) were significantly increased (P < 0.05) in High group compared to other groups. The tight junctions and pro-apoptosis related genes' expression significantly decreased (P < 0.05) in High group, and high dose caused a disruption of intestinal villi integrity and tissue injury in the jejunum of mice. In addition, the enumerations of C. perfringens, Escherichia coli, and Lactobacillus explained why the gut of High group mice was seriously damaged, because the C. perfringens and Escherichia coli significantly enriched (P < 0.05), and Lactobacillus dramatically decreased (P < 0.05). Overall, our results provide an experimental and theoretical basis for understanding the pathogenesis and exploring the effects of porcine C. perfringens on mice.