(comfrey) is a perennial herb native to West Asia and Europe. Its root extracts are commonly used as a natural remedy to treat muscle, joint, skin, and bone disorders, especially in Europe. However, more information is needed on the biomedical functions of comfrey leaves. This study’s sequencing results of internal transcribed spacer and trnL−trnF genes showed that plants purchased from the local market were comfrey and named S. officinale WL (WL). The suitable extraction conditions of the WL leaves with the highest extract yield and total phenols and flavonoid contents by microwave-assisted extraction were identified. The antioxidative and anti-inflammatory activities and possible molecular mechanism(s) of the WL leaf extract (WLE) were evaluated. Furthermore, the major component of WLE was identified as rosmarinic acid by HPLC. Results showed that the optimal extract condition was obtained with 750 W microwave power, 50 °C, 75% methanol, the solid-to-solvent ratio of 1:10, and 15 min. Results of all DPPH, ABTS, and superoxide radical scavenging activities, reducing power, ferrous ion chelating activity, and ferric reducing antioxidant power showed high antioxidative capacities of WLE. Furthermore, WLE showed prominent DNA-protecting activity. WLE attenuated lipopolysaccharide-stimulated inflammation by suppressing iNOS, COX-2, IL-1β, IL-6, and TNF-α expressions in the RAW264.7 macrophages. These attenuations are involved in the inactivation of lipopolysaccharide-stimulated NF-κB and MAPK signaling pathways. Therefore, the comfrey leaf extract obtained via a time- and energy-saving microwave-assisted extraction may be a potential antioxidative and anti-inflammatory biomedicinal agent.