Introduction Cytoreductive surgery (CRS) with subsequent hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising modality to treat and prevent peritoneal metastases. However, this treatment is associated with signficant morbidity and mortality. Whether or not CRS with HIPEC interferes with anastomotic healing has also been debated. This study was designed to investigate the effects of mitomycin C, cisplatin, oxaliplatin, and doxorubicin used in HIPEC treatment on colonic anastomosis healing in a rat model. Methods Sixty Wistar albino rats were employed in the study. Sigmoid resection and end-to-end colorectal anastomosis was performed in all rats. Group 1 rats underwent the surgical procedure alone, while group 2 rats were given hyperthermic intraperitoneal lavage with heated saline following surgery. Groups 3, 4, 5, and 6 had surgery with concomitant HIPEC treatment with mitomycin C, cisplatin, oxaliplatin, and doxorubicin, respectively. Anastomotic bursting pressures and hydroxyproline levels were evaluated. Results Regarding the hydroxyproline levels, groups 1 and 2 showed significantly higher values than other groups (p<0.001). However, there was no significant difference between the HIPEC treatment groups (groups 3, 4, 5, and 6) (p>0.05). When groups were compared regarding bursting pressure values, no significant differences were observed (p = 0.81). Conclusions This study demonstrated that the HIPEC procedure with mitomycin C, cisplatin, oxaliplatin and doxorubicin had negative effects on hydroxyproline levels, but had no detrimental effect on anastomotic bursting pressure in a rat model.