Despite the development of new biological and synthetic targeted therapies, methotrexate remains one of the most commonly used immunomodulatory drugs in rheumatology. However, its effect on the immunogenicity of vaccines has been studied only to a limited extent until recently, resulting in the lack of clear guidelines on the use of methotrexate during vaccination. Significant progress was made during the COVID-19 pandemic due to the dynamic development of research on vaccines, including patients with autoimmune inflammatory rheumatic diseases. In the following literature review, we present a summary of what we know so far on the impact of methotrexate on post-vaccination response in adult rheumatology patients, taking into account the lessons learned from the COVID-19 pandemic. Studies on the effect of methotrexate on the immunogenicity of influenza, pneumococcal, herpes zoster, tetanus/diphtheria/pertussis, hepatitis A, yellow fever, and COVID-19 vaccines are described in detail, including the effect of methotrexate on the humoral and cellular response of individual vaccines. The available evidence for recommendations for withholding methotrexate in the post-vaccination period is presented. Lastly, an overview of potential immunological mechanisms through which MTX modulates the immunogenicity of vaccinations is also provided.