Background: Oncology patients experience a large number of symptoms and, those referring to cognitive performance has an ever-increasing importance in clinical practice, due to the increase in survival rates and interest in the patient’s quality of life. The studies reviewed showed that chemotherapy-related cognitive impairment might occur in 15 and 50% of oncology patients. The main objective of this research was to study the impact of chemotherapy on the cognitive function of patients with locoregional breast cancer. Method: Analytical, prospective, longitudinal study using three measures, unifactorial intrasubject design, non-probability, and random selection sampling. The sample comprised women newly diagnosed with locoregional breast cancer in stages I, II, IIIA who received chemotherapy at the University Hospital of Salamanca (Complejo Asistencial Universitario de Salamanca), randomly selected for three years. Semi-structured interviews were conducted, and anxiety and depression (Hospital Anxiety and Depression scale, HAD); quality of life (QLQ-BR23 scale) and the following cognitive variables were assessed—processing speed, attention, memory, and executive functions (subtests of the Wechsler Intelligence Scale and the Trail Making Test). Results: The final sample size included 151 participants; 23 were excluded. A decline in cognitive performance was observed in patients, which did not completely recover two months after chemotherapy was completed. Additionally, worse cognitive performance was observed in patients with anxious or depressive symptoms. There was a negative impact on the quality of life. Conclusion: Chemotherapy had an impact on the cognitive performance of oncology patients in most cognitive domains studied.