The plant Angelica archangelica, owing to its magnificent therapeutic effectiveness in folklore medicine system, has been regarded as an “angel plant.” The current investigation was aimed to optimize extraction conditions of A. archangelica roots and to investigate in vivo role of optimized extract in fibromyalgia. Plant material (dried roots) was subjected to methanol extraction at variable temperature (40 to 60 °C) and time (12 to 36 hr) conditions as per two-factorial design strategy, and responses in terms of antioxidant activity were determined. The optimized extraction conditions were found to be temperature of 60 °C and time of 36 hr. HPLC fingerprinting indicated the presence of coumarins in extract. To induce fibromyalgia, the mice were administered reserpine at a dose of 0.5 mg/kg. Mice were orally treated with 100, 200, and 400 mg/kg extract, and magnitude of fibromyalgia was quantified. In comparison to reserpine group, the extract treatment attenuated pain as shown by significant increase in paw withdrawal threshold against mechanical stimuli (P < 0.05), improved motor ability indicated by increase in fall-off time in inclined plane test (P < 0.05), improved locomotion indicated by increased square crossings in open field test (P < 0.05), and improved cognition as shown by significant reduction in time to reach platform in Morris water maze test and passive avoidance task test (P < 0.05). Extract treatment significantly halted reserpine-induced rise in serum cytokine level (P < 0.05) and brain oxidative stress (P < 0.05). Angelica archangelica extract exerted its beneficial effects in fibromyalgia possibly through the attenuation of oxidative stress-mediated inflammatory cascade. PRACTICAL APPLICATION: Leads from natural products have become an integral part of drug designing processes and have high acceptability due to their better tolerance. The optimization of extraction conditions of plant yields better results and could reduce the processing time, thus increasing its industrial value.© 2020 Institute of Food Technologists®.