Purpose: To observe and evaluate the clinical efficacy of the Wisconsin ginseng (Panax quinquefolius) herbal botanical adjunctive treatment to improve Rheumatoid Arthritis (RA) fatigue. A secondary aim was to observe RA related biomarkers and evaluate the safety of the treatment. Methods: Eligible adult patients with RA were enrolled between September 2019 and January 2020 at a multisite in a double-blind randomized trial with each intervention lasting 8 weeks with prescription medications, diet, and lifestyle kept constant. Interventions consisted of Wisconsin ginseng in doses of 3,000, or 6,000 mg/day or placebo given in twice daily dosing over 8 weeks. Primary endpoint outcome measures were changes from baseline at 4 and 8 weeks utilizing the Visual analogue scale to evaluate fatigue severity (VAS-F) and Disease activity score 28-joint count erythrocyte sedimentation rate & C-reactive protein (DAS28 ESR & CRP), secondary objectives included The health assessment questionnaire disability index (HAQ-DI), Cyclic adenosine monophosphate (cAMP), and Cyclic guanosine monophosphate (cGMP). Safety parameters included complete blood count (CBC), liver, kidney and function. Results: A total of 17 individuals with well-controlled RA that complained of fatigue completed the study. The safety profiles were unaffected. Kruskal-Wallis test was used to compare the efficacy at 4 weeks and 8 weeks after treatment, there was no significant difference in efficacy between the groups 4 weeks after treatment (Z=2.914, P=0.233). After 8 weeks of treatment, there was a significant difference in efficacy between the groups (Z=6.753, P=0.034). Further pair comparison showed that the effect of the high-dose 6,000 mg/day group demonstrated greater efficacy than the control group (Z=6.325, P=0.01). Conclusions: Addition of Wisconsin ginseng to conventional therapy in RA with fatigue, thus warrants further investigation to guide the role of Wisconsin ginseng to improve fatigue associated with autoimmune disorders as an adjunct treatment. Trial registration: Chinese Clinical Trials Registry. Identifier: ChiCTR1900026257; Registration Date: 2019-09-28.