Japanese knotweed (Reynoutria japonica Houtt.) is Poland’s invasive weed, for which there is no efficient control method. The rhizomes of this species are rich in resveratrol. In this work, we evaluated (1) the effectiveness of electromagnetic microwaves (MV) in destroying Japanese knotweed using an original device, HOGWEED (MV of 2450 MHz), (2) the ecotoxic effect of the MV on the soil environment, and (3) the resveratrol content in knotweed rhizomes after MV treatment. The field studies were carried out in 2022 in southern Poland. Cut plants were MV-treated for times of 5.0–25.0 min. The MV efficiency was checked 10 and 56 days after treatment (DAT). After MV treatment, fresh soil samples were taken to analyze their ecotoxicity. As a result, at 56 DAT, knotweed was controlled if MV was used for at least 20.0 min. The MV did not affect the soil ecotoxicity. The MV-treated soils were classified as non-toxic or low-toxic. To analyze the resveratrol content, healthy knotweed rhizomes were dug out, treated with MV in the laboratory at 2.5–10.0 min, and analyzed for resveratrol content in HPLC-MS/MS. As a result, the resveratrol in the rhizomes significantly decreased in a time-dependent manner following MV exposure.