Interleukin-5 (IL-5) strongly initiates the asthmatic inflammatory response, which affects 300 million patients with asthma annually worldwide, through oxidative stress generation. Citrus flavonoids have beneficial properties, such as anti-inflammatory and antioxidant properties, but the precise molecular mechanism of the inhibition of the asthmatic inflammatory response is still unclear. This study aimed to investigate the underlying mechanisms of ROS and IL-5 reduction with citrus flavonoid treatment in PMA/ionomycin-induced EL-4 cells. Our results showed that hesperetin and gardenin A dramatically suppressed ROS and IL-5 production through distinct pathways. Interestingly, hesperidin induced HO-1 expression through the transcription factor Nrf2 coupled with the PI3K/AKT or ERK/JNK signaling pathway, consequently downregulating NFAT activity and IL-5 secretion. Likewise, gardenin A induced HO-1 expression and subsequently suppressed IL-5 production by reducing NFAT activity and upregulating PPARγ in EL-4 cells, suggesting that inducing HO-1 expression may inhibit asthmatic inflammation. Altogether, hesperidin and gardenin A have great potential for regulating the asthma-associated immune responses through antioxidant properties.