Aims: This study evaluated the cost-utility of subcutaneous versus oral methotrexate for rheumatoid arthritis (RA) management in Portugal. Methods: A cost-utility analysis (CUA) was conducted over a lifetime horizon from the Portuguese National Health Service perspective, adapting a model previously published for the United Kingdom. Patients were modelled to transition through lines of therapy including conventional synthetic, followed by biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs). In the base case, first-line subcutaneous methotrexate was compared with first-line oral methotrexate, while a scenario analysis explored second-line subcutaneous methotrexate use, after failing first-line oral methotrexate. Clinical, quality-of-life, and cost data were sourced from the literature, using Portuguese data where available. Projected costs and benefits were combined in net monetary benefit (NMB) estimates, evaluated against a willingness-to-pay threshold of €50,000 per quality-adjusted life-year (QALY) gained. The robustness of results was explored in sensitivity and scenario analyses. Results: First-line subcutaneous methotrexate was projected to yield an additional 0.25 life-years and 0.55 QALYs, while reducing total costs by €11,108 over patients’ lifetimes, relative to first-line oral methotrexate. Using subcutaneous methotrexate after first-line oral methotrexate was associated with gains in life expectancy (+0.54 life-years) and quality-adjusted life expectancy (+1.19 QALYs), while also reducing projected costs (−€25,892). In both analyses, subcutaneous methotrexate was therefore associated with improved effectiveness and reduced total costs. The corresponding NMBs were €38,821 and €85,485, respectively. Health gains resulted from more patient time spent on active treatment, with improved disease control, and consequently better health-related quality of life and reduced mortality risk. Improved disease control also implied reduced hospitalization costs, with costs further reduced due to delaying, or avoiding, costly biologics, which offset higher subcutaneous methotrexate acquisition costs. Sensitivity and scenario analyses confirmed base case results, including for different later-line biologic treatments, clinical response data, and time horizons. Conclusions: This CUA evaluated the value-for money of subcutaneous versus oral methotrexate for RA management in Portugal and found that subcutaneous methotrexate is likely a cost-effective strategy, with the potential to reduce healthcare expenditure and improve patient outcomes. These findings support consideration of wider adoption of subcutaneous methotrexate within Portuguese clinical practice.