<b><i>Introduction:</i></b> This study was conducted to develop and validate a nomogram for predicting the risk of neutropenia or febrile neutropenia (FN) in tumor patients in the first cycle of etoposide-based chemotherapy. <b><i>Methods:</i></b> This retrospective cohort study used an information system to monitor patients with non-Hodgkin’s lymphoma or solid tumors receiving an etoposide regimen in the first chemotherapy cycle in our hospital from 2009 to 2020. Binary logistic regression analysis was used to identify the influencing factors of patients with neutropenia or FN. Those factors were then used to develop a nomogram. <b><i>Results:</i></b> A total of 1,554 patients were divided into the development group (<i>n</i> = 1,072) and validation group (<i>n</i> = 482). Variables used to predict neutropenia or FN were Karnofsky performance status (odds ratio [OR] = 0.85, 95% confidence interval [CI] = 0.81–0.89, <i>p</i> < 0.01), metastatic sites ≥3 (OR = 6.33, 95% CI = 2.66–15.11, <i>p</i> < 0.01), comorbidity of heart disease (OR = 4.88, 95% CI = 1.74–13.67, <i>p</i> < 0.01), recent surgery (OR = 7.96, 95% CI = 1.96–32.36, <i>p</i> < 0.01), administration of alkylating agents (OR = 4.50, 95% CI = 1.10–18.48, <i>p</i> < 0.01), total bilirubin ≥25 μmol/L (OR = 11.42, 95% CI = 4.00–32.61, <i>p</i> < 0.01), and lymphocyte count <0.7 × 10<sup>9</sup>/L (OR = 4.22, 95% CI = 2.00–9.75, <i>p</i> < 0.01). <b><i>Conclusion:</i></b> This model can aid the early identification and screening of the potential risk of neutropenia or FN in the first cycle of treatment for patients using etoposide-based chemotherapy.