Background and Objectives: Obesity is currently a major health problem due to fatty acid accumulation and excess intake of energy, which leads to an increase in oxidative stress, particularly in the liver. The main goal of this study is to evaluate the protective effects of spirulina (SP) against cafeteria diet (CD)-induced obesity, oxidative stress, and lipotoxicity in rats. Materials and Methods: The rats were divided into four groups and received daily treatments for eight weeks as follows: control group fed a standard diet (SD 360 g/d); cafeteria diet group (CD 360 g/d); spirulina group (SP 500 mg/kg); and CD + SP group (500 mg/kg, b.w., p.o.) according to body weight (b.w.) per oral (p.o.). Results: Our results show that treatment with a CD increased the weights of the body, liver, and abdominal fat. Additionally, severe hepatic alteration, disturbances in the metabolic parameters of serum, and lipotoxicity associated with oxidative stress in response to the CD-induced obesity were observed. However, SP treatment significantly reduced the liver alteration of CD feed and lipid profile disorder associated with obesity. Conclusions: Our findings suggest that spirulina has a marked potential therapeutic effect against obesity and mitigates disturbances in liver function parameters, histological alterations, and oxidative stress status.