Gastroesophageal reflux disease (GERD) is a prevalent chronic condition affecting the well-being of both adults and children in general medical practice. Research on the effects of fermented soybean (SB) supplementation in managing GERD is relatively new, with limited studies available. The existing research often lacks sufficient dosing regimens and study durations to differentiate between transient placebo effects and sustained benefits. In this study, the beneficial effects of FSB supplementation were investigated in 110 voluntary participants (NCT06524271). The participants were required to take 1 g of FSB supplement once daily for 12 weeks. GERD symptoms were evaluated using the Reflux Disease Questionnaire (RDQ), while inflammatory markers, including interleukin-4 (IL-4), interleukin-6 (IL-6), and interleukin-8 (IL-8), were measured to assess inflammation. The Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire was used to evaluate participants’ quality of life. The results indicated that FSB supplementation significantly (p < 0.05) alleviated heartburn and regurgitation symptoms and reduced levels of IL-4, IL-6, and IL-8, indicating a notable anti-inflammatory effect. Additionally, significant (p < 0.05) improvements were observed in QOLRAD scores, particularly in vitality, emotional distress, and physical/social functioning. Collectively, our findings support the use of FSB as an adjuvant approach in managing GERD, with notable improvements in patients’ quality of life.