The introduction of combination chemotherapy raised the survival rate of cancer patients. However, it is associated with chemotherapy-induced cognitive impairment, often referred to as "chemobrain", which is a distressing adverse effect of cancer treatment. Doxorubicin and cyclophosphamide, two widely used chemotherapeutic agents in the treatment of various malignancies, have been shown to induce cognitive dysfunction. This review explores the underlying mechanisms that contribute to the chemobrain induced by doxorubicin and cyclophosphamide combination therapy, shedding light on oxidative stress, inflammation, neurotransmitter dysregulation, and neuroinflammation. Studies have shown that chemobrain is associated with activated inflammation and oxidative damage in the hippocampus. We also delve into the molecular pathways activated by doxorubicin and cyclophosphamide, such as the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways, which are implicated in cognitive dysfunction. Additionally, this article explores protective approaches, including antioxidants like L-carnitine, polyphenolic-rich compounds from Thunbergia erecta, and N-acetylcysteine, offering potential solutions for alleviating doxorubicin and cyclophosphamide-induced chemobrain. Notably, these protective agents, although promising in pre-clinical models, await clinical investigation. Therefore, there is a gap in data to support the application of any neuroprotective medication in a clinical context. Thus, clinical trials are necessary to assess their therapeutic potential. In conclusion, this review integrates data from diverse studies to elucidate the mechanisms and suggests potential protective strategies, offering insights for researchers seeking to alleviate cognitive challenges in doxorubicin and cyclophosphamide-treated cancer patients.