Purpose <p>This phase I/II study aimed to determine the maximum-tolerated dose (MTD) of intrathecal pemetrexed (IP) with vitamin supplementation, and to evaluate its safety, feasibility and therapeutic activity for newly diagnosed leptomeningeal metastasis (LM) from solid tumors.</p> Methods <p>The phase I study followed the classic 3 + 3 design, with IP dose escalating from 15&#xa0;mg. The recommended dose was applied in the phase II study. IP was administered first as induction therapy twice weekly for 2 weeks, followed by consolidation therapy, once weekly for 4 weeks, then maintenance therapy once monthly. Vitamin supplementation was initiated prior to the first IP dose. The MTD, adverse events (AEs), overall survival (OS), clinical response rate (CRR) and disease control rate (DCR) were evaluated.</p> Results <p>A total of 34 patients were enrolled. In the phase I study, 2 patients in the 20&#xa0;mg group experienced dose-limiting toxicity, including grade 4 leukopenia and grade 5 chemical arachnoiditis. The MTD was established as 15&#xa0;mg. Among 28 patients in the MTD group, 24 completed induction therapy, 19 completed consolidation therapy and 11 proceeded to maintenance therapy. The overall AEs rate was 74% (25/34), and severe AEs rate (&gt; grade 3) was 15% (5/34). In the MTD group, the CRR, DCR and median OS were 46% (13/28), 75% (21/28) and 8.1 months (95% CI, 6.5–11.9).</p> Conclusion <p>IP at 15&#xa0;mg, with folic acid and vitamin B12 supplementation initiated before the first IP dose, demonstrated feasibility and exhibited controllable toxicity. This regimen offers a new treatment option with therapeutic activity for newly diagnosed LM patients with solid tumors.</p> Trial registration <p><a href="http://ClinicalTrials.gov">ClinicalTrials.gov</a> Identifier NCT05289908.</p>