The key role of the NF-κB/MAPK signaling pathway in the pathogenesis and development of inflammation has been demonstrated in several studies [22,34,35,36]. The phosphorylation of some transcription factors and proteins, such as NF-κb, Iκb-α, p38 and JNK, is the typical feature of the activated NF-κB/MAPK signaling pathway [34]. As there are very limited reliable antibodies against zebrafish, the bioactive mechanisms of functional components in most studies based on zebrafish models are mainly evaluated by detecting the expression levels of inflammation-related cytokines using qRT-PCR (with high sensitivity, specificity and accuracy). Therefore, the expression levels of five pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-12 and TNF-α) and one anti-inflammatory cytokine (IL-10) in the NF-κB/MAPK signaling pathway in zebrafish were examined by qRT-PCR to explore the potential anti-inflammatory mechanisms of GPs and GP–Zn (II) complexes. As shown in Figure 6, the mRNA expression levels of IL-1β, IL-6, IL-8, IL-12 and TNF-α were upregulated significantly by 0.56–5.14-fold in CuSO4-induced zebrafish compared with the control group, accompanied by a significant decrease in the expression of IL-10 (p4 induced a severe inflammatory response by disrupting the balance of pro-inflammatory and anti-inflammatory cytokines in the NF-κB/MAPK signaling pathway. After the administration of GPs and their Zn (II) derivatives (concentration: 5–100 µg/mL), the mRNA expression levels of five pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-12 and TNF-α) were effectively inhibited by 6.88–29.91%, 16.59–49.94%, 13.63–43.45%, 30.61–61.64% and 36.09–83.37%, respectively, while the expression of anti-inflammatory cytokine (IL-10) was significantly promoted by 0.96–2.46-fold in zebrafish. It was reported that ginger polysaccharides alleviated the intestinal inflammation symptoms and inhibited the production of pro-inflammatory cytokines (e.g., TNF-α, IL-1β and IL-6) in dextran sulfate sodium-induced ulcerative colitis mouse model, which was in accordance with our findings [37]. Among the six pro-/anti-inflammatory cytokines, the changes of TNF-α stimulated by CuSO4 but alleviated by GPs and their Zn (II) derivatives were the most significant, with a 5.14-fold increase in the expression level compared with the control group, but a 36.09–83.37% down-regulation compared with CuSO4-induced inflammatory zebrafish. In the low and high dose groups of GP–Zn (II) complexes (5 µg/mL and 100 µg/mL), the expression levels of TNF-α were close to those of the blank control group, with no significant differences (p > 0.05).Although GP–Zn (II) complexes exerted significantly (5 μg/mL) or insignificantly (10 and 100 μg/mL) higher anti-inflammatory activity than GPs, some inflammatory cytokines did not follow the similar trend. Overall, the modified GP–Zn (II) derivatives exhibited a higher regulation on the expression levels of IL-6, IL-8, TNF-α and IL-10, but a lower inhibition on the expression of IL-1β and IL-12. The reason might be that GPs and their Zn (II) complexes had different regulatory mechanisms on the inflammatory response or their main regulatory pathways were different, despite having some of the same targets [22]. Notably, the regulation of the mRNA expression levels of these inflammation-related cytokines by GPs and GP–Zn (II) complexes was not always dose-dependent, which was similar to other studies [22,38]. In general, the dose-bioactivity relationship showed a parabolic pattern, with an optimal dose at the apex. As the sample concentration increased from 5 μg/mL to 100 μg/mL, the continuously increasing inhibition on the pro-inflammatory cytokines suggested that the optimal dose was closer to 100 μg/mL (the apex of the parabola), while the trend of increasing and then decreasing modulation on inflammation indicated that the optimal dose was closer to 10 μg/mL. Therefore, the effect of GPs and GP–Zn (II) complexes on these inflammation-related cytokines was not always dose-dependent. In summary, GPs and GP–Zn (II) complexes might exert anti-inflammatory activity by down-regulating the mRNA expression levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-12 and TNF-α) and upregulating the expression of anti-inflammatory cytokine (IL-10).