Background: Non-Hodgkin’s lymphoma (NHLs) is a prevalent type of cancer for which Intravenous (IV) Rituximab is a widely used treatment option. Nevertheless, IV infusions can lead to intense resource use and, subsequently, costs. Given that a subcutaneous (SC) therapeutically equivalent formulation of the drug is currently available, this study aimed to examine the potential clinical and economic value of the introduction of the SC formulation for the Greek healthcare setting. Methods: A cost-minimization and budget-impact analysis contributed to comparing staff, patient time and resource utilization and estimating the clinical effects and associated costs in the IV and SC administration. A questionnaire-based survey was used to provide data regarding the local treatment patterns and the resource use associated with each treatment in the Greek NHS. The analysis followed the third-party payer perspective, and cost data relevant to personnel salaries, pharmaceuticals and resource utilization were obtained from official government sources. Results: SC administration was associated with time savings in activities such as pre-medication administration (3 minutes saved with the SC use), monitoring during infusion (12 minutes for physicians and 3 minutes for nurses) as well as time-savings in the preparation of the drugs, the actual dispensing process and the post-injecting monitoring processes. A significant decrease was observed in the nursing and chair time (57% and 90% per case, respectively) and a higher level of services could be secured in terms of hospital capacity with the SC use. SC administration was found to generate budget savings of 618,708€ per 1000 patients/3 years over the full course of treatment. Conclusions: Switching IV to SC administration, as demonstrated in the case of Rituximab for NHLs in Greece, can reduce staff time and administration costs, improve the capacity of the system and, possibly, improve resource allocation in the healthcare system.