Chemotherapy-induced cognitive impairment (CICI), commonly referred to as chemobrain, is a prevalent side effect of cancer treatment that severely affects survivors' quality of life. Chemotherapeutic agents, including cisplatin, doxorubicin, and paclitaxel, cross the blood-brain barrier (BBB) and induce neurotoxicity, resulting in cognitive dysfunction. These agents trigger reactive oxygen species (ROS) generation, cause mitochondrial dysfunction, and induce DNA damage, all of which impair synaptic plasticity and neurogenesis. Mitochondrial dysfunction is central to chemobrain, as it disrupts ATP production, increases oxidative stress, and leads to neuronal apoptosis. Furthermore, mitochondrial DNA (mtDNA) damage caused by agents like cisplatin impairs oxidative phosphorylation, exacerbating neuronal degeneration. The molecular mechanisms of chemobrain likely involve several key players, including NAMPT-dependent NAD+ depletion and increased levels of Cyclooxygenase-2 (COX-2), which collectively exacerbate oxidative stress and neuroinflammation. Another important molecular target is the Adenosine A2A receptor (A2AR). When activated, it contributes to synaptic dysfunction and cognitive decline, particularly in chemotherapy-related cognitive deficits in the hippocampus. This review explores the complex interplay of these core pathologies in chemobrain and discusses how targeting these pathways could offer a therapeutic strategy to alleviate cognitive impairments in cancer survivors.