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What is known and objective: Low‐dose methotrexate (LDMTX) has been widely used for many decades in clinical settings, with good safety profiles compared with those of high‐dose methotrexate. LDMTX is also used as one of the off‐label conservative therapies in treating placenta accreta (PA). Until now, only a few mild adverse drug reactions (ADRs) have been published after short‐term use of LDMTX, and no severe cases have been reported. Case summary: We present a case of a 30‐year‐old female who developed acute severe oral ulcerative mucositis with degree IV myelosuppression and degree III hepatic injury, after three doses of LDMTX to treat placenta accrete. The symptoms gradually improved after leucovorin rescue and supportive treatments. What is new and conclusion: The present case provides the first severe ADR report for the short‐term use of LDMTX for treating PA, indicating that potentially life‐threatening complications can also occur when using LDMTX. Early recognition and immediate leucovorin rescue could result in a favourable outcome. [ABSTRACT FROM AUTHOR]