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Piper guineense contains a variety of alkaloids and flavonoids each with its own unique biological activity. Understanding the molecular mechanisms underlying the effects of Piper guineense on gene expression in and enzyme activity in Drosophila melanogaster could have significant implications in public health. Therefore, the aim of this study was to determine the effect of varied concentration of Piper guineense on SRP gene expression in mediating Hematopoiesis and catalase activity in Drosophila melanogaster. A total of one hundred and forty (140) flies were divided into four (4) groups; A, B, C and D representing 100mg group, 200mg group, control and 400mg group. mRNA of SRP and catalase activity was determined using polymerase chain reaction and colorimetric method respectively. Data generated was analyzed using graph pad prism (version 8.02, California, USA). The result showed that there was significant decrease (p<0.01) in SRP expression in the group administered 100mg ofPiper guineensewhen compared to the control group. The experimental group that received 400mg had a significantly higher (p<0.01) SRP expression when compared to control, 100mg and 200mg administered groups. For the catalase activity, there was no significant difference (p>0.05) in catalase activity of Drosophila melanogaster administered 100mg ofPiper guineense when compared to control. The groups administered 200mg (2.97±0.61) and 400mg (3.41±0.08) of Piper guineense had significantly lower catalase levels when compared to control (6.53±0.51) (p<0.05). In conclusion, Piper guineense caused a dose-dependent modulation of SRP expression with reduction of catalase activity at 200mg and 400mg dosage of the extract.