Therapeutic use of chemotherapy has led to a significant increase in the number of cancer survivors worldwide. Due to its increased use, the adverse effects, especially on brain function, have been able to be observed. Chemotherapy often causes symptoms of cognitive decline as characterized by the impairment of verbal memory, executive function, visuospatial functioning, and short-term memory. These debilitating neurological consequences of chemotherapy are referred to as chemobrain. Despite the attention focused on chemobrain over the past few decades, the biological understanding regarding the proposed molecular pathogenesis of chemobrain remains fragmentary. Understanding the mechanisms underlying the development of chemobrain would assist the prevention or treatment of the adverse effects of chemotherapy on brain function. In a clinical setting, limitations regarding sample collection, the heterogeneity of cancer patients, and exogenous confounding factors hamper clinical examination of chemobrain in actual cancer patients. A preclinical model with experimental animals facilitates the holistic exploration regarding the underlying mechanisms of chemobrain without the interfering factors found in patients. This review comprehensively compiles the existing candidate mechanisms of chemobrain observed in animal studies with an attempt to gain mechanistic insight into the condition. In addition to considering biological pathways, we also summarize promising therapeutic strategies to alleviate symptoms of chemobrain which have already been proven to provide effective neuroprotection in chemobrain models.