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Mild-to-moderate ulcerative colitis (UC) management is centred on 5-aminosalicylic acid (5-ASA) derivatives. Whether supplementing 5-ASA with nutraceuticals can provide real advantages in UC-relevant outcomes is unclear. This retrospective multicentre study compared clinical remission, response rates, and faecal calprotectin levels in a two-arm design, including patients treated with 5-ASA alone and those with additional <i>H. erinaceus</i>-based multi-compound supplementation. In the 5-ASA alone group, clinical response rates were 41% at three months (T₁) and 60.2% at six months (T₂), while corresponding clinical remission rates were 16.9% and 36.1%. In the nutraceutical supplementation group, clinical response rates were 49.6% (T₁) and 70.4% (T₂), with clinical remission rates of 30.4% (T₁) and 50.9% (T₂). No significant differences in clinical response rates between the groups at T₁ (<i>p</i> = 0.231) and T₂ (<i>p</i> = 0.143) emerged. Clinical remission rates differed significantly at both time points (<i>p</i> = 0.029 and <i>p</i> = 0.042, respectively). Faecal calprotectin levels decreased significantly in both groups during the retrospective follow-up (<i>p</i> < 0.05), and this was more pronounced in nutraceutical supplementation patients at both T₁ (<i>p</i> = 0.005) and T₂ (<i>p</i> = 0.01). No adverse events were reported. This multi-component nutraceutical supplementation offers real-world potential in controlling disease activity in patients with mild-to-moderate UC.