Background/Objectives: Chemotherapy can negatively affect cognitive functioning through direct and indirect mechanisms, with 15–50% of patients experiencing a decline that impacts quality of life. While neurocognitive tests are the main assessment tool, self-reported measures provide valuable additional insights. The aim of this study was to evaluate the cognitive decline of patients during the early stages of chemotherapy treatment and its impact on their quality of life, as well as to outline future perspectives for an early intervention model. Materials and Methods: This prospective longitudinal study was conducted on 40 patients aged 18 to 64 years. Data were collected using the FACT-Cog v.3 questionnaire, administered at the beginning of the first chemotherapy cycle (T0), and then again after approximately 3–4 weeks (T1) and 6–8 weeks (T2). Results: The data show a progressive decline in perceived cognitive abilities (PCI: 72.10 → 64.43; PCA: 25.70 → 20.90) and overall quality of life (9.73 → 8.75) from T0 to T2. A significant positive correlation was found between perceived cognitive abilities and quality of life, supporting the link between cognitive decline and quality of life. Questionnaire variables reliably predicted changes in quality of life two months after chemotherapy [F(4, 35) = 3.91, p = 0.01]. Conclusions: The findings show a decline in quality of life as chemotherapy progresses. However, this decline can be predicted from the second month of treatment using the FACT-Cog v.3 questionnaire. The findings further highlight even more the value of integrating early empowerment, rehabilitative and psychoeducational programs to mitigate cognitive decline and improve quality of life.