Pluchea indica (L.) Less. leaf has a long history of being used as a food and in traditional medicines. Although gamma irradiation is an effective decontamination method, it must be performed appropriately to preserve the bioactive constituents and biological activities of the plant. This study investigated the influence of gamma irradiation on the caffeoylquinic acid derivatives content, antioxidant capacity, and microbial burden of P. indica leaf. Dried P. indica leaf powder was exposed to gamma rays from cobalt-60 at the absorbed doses of 2.5, 5.0, 7.5, and 10 kGy. After a maceration of P. indica leaf with 70% ethanol, the content of six caffeoylquinic acid derivatives (CQAs) in the extract was assayed using high-performance liquid chromatography. The antioxidant capacity of the ethanolic extract was also determined using the DPPH, ABTS, and ferric reducing antioxidant power (FRAP) methods. The total aerobic bacteria and total yeast and mold counts were investigated using the Petrifilm method at 0 and 3 months after irradiation. Doses of 5–10 kGy significantly increased the CQA level (P < 0.05). The antioxidant activity was enhanced significantly at 2.5–10 kGy (P < 0.05). Doses of 2.5–10 kGy also effectively reduced the microbial load (P < 0.05). Among the irradiation doses, 10 kGy showed the best results. Thus, gamma irradiation at 10 kGy is useful in increasing CQA content and antioxidant capacity as well as reducing the microbial load of P. indica leaf.