Introduction: In several studies, the chimeric antigen receptor T‐cell therapy tisagenlecleucel demonstrated encouraging rates of remission and lasting survival benefits in pediatric patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL). We assessed the cost‐effectiveness of tisagenlecleucel (list price: 320 000 EUR) among these patients when compared to clofarabine monotherapy (Clo‐M), clofarabine combination therapy (Clo‐C), and blinatumomab (Blina) from both a healthcare and a societal perspective. We also assessed future medical and future non‐medical consumption costs. Methods: A three‐state partitioned survival model was used to simulate a cohort of pediatric patients (12 years of age) through different disease states until the end of life (lifetime horizon). Relevant outcomes were life years, quality‐adjusted life years (QALYs), healthcare costs, societal costs, and the incremental cost‐effectiveness ratio (ICER). Uncertainty was explored through deterministic and probabilistic sensitivity analyses as well as through several scenario analyzes. Results: Total discounted costs for tisagenlecleucel were 552 679 EUR from a societal perspective, which was much higher than the total discounted costs from a healthcare perspective (ie, 409 563 EUR). Total discounted societal costs for the comparator regimens ranged between 160 803 EUR for Clo‐M and 267 259 EUR for Blina. Highest QALYs were estimated for tisagenlecleucel (11.26), followed by Blina (2.25), Clo‐C (1.70) and Clo‐M (0.74). Discounted societal ICERs of tisagenlecleucel ranged between 31 682 EUR/QALY for Blina and 37 531 EUR/QALY for Clo‐C and were considered cost‐effective with a willingness‐to‐pay (WTP) threshold of 80 000 EUR/QALY. None of the scenarios exceeded this threshold, and more than 98% of the iterations in the probabilistic sensitivity analysis were cost‐effective. Discussion: At the current price and WTP threshold, tisagenlecleucel is cost‐effective from both a healthcare and a societal perspective. Nevertheless, long‐term effectiveness data are needed to validate the several assumptions that were necessary for this model.