This study aimed to identify the gene expression profiling of lipid related genes in animal model of obesity and the role of microalgal Dunaliella salina (alga) in modulating the expression of these genes during the initial period of obesity. The diet-induced obesity model was used using fifty male Wistar albino rats (weighing 150-160 g) that have obesity caused by being fed high-fat diet (HFD) for 12 weeks. These rats were randomly divided into 2 groups (10 rats each) and treated with D. salina extract and orlistat for 6 weeks. The anti-obesity effect of this halophilic unicellular green alga was compared to orlistat, a standard anti-obesity drug promoting weight loss as a gastric and pancreatic lipase inhibitor. Treatment with the alga and orlistat showed significant effect in reducing gastric inhibitory polypeptide (GIP). Also, the treatment of obesity-induced rats with the alga increased significantly the mRNA expression levels of lipid catabolic genes (peroxisome proliferator-activated receptor PPAR-α and carnitine palmitoyltransferase CPT-1) and decreased significantly the expression levels of lipid anabolic gene (SCD-1) compared with obesity-induced rats. In addition, D. salina extract was able to decrease ROS generation and inhibit the rate of DNA damage in obese rats. The study was extended to evaluate the phytochemical composition of microalgal extract. The fatty acid methyl esters were analyzed by GLC. The extract contained considerable level of omega-3 fatty acids. The presence of palmitic (62.5%), linolenic (9%), oleic (8.6%) and linoleic (7.4%) was revealed. The percentage of saturated and unsaturated fatty acids were 67.7 and 32.1%, respectively. D. salina extract administration which is rich in omega-3 fatty acids, has anti-obesity properties. Results suggested that D. salina might be available as functional alga and bioactive diet supplement for the treatment of obesity.