The pharmacological significance of acha (Digitaria exilis) and black cumin (Nigella sativa) in fostering sound mental health has been demonstrated in several researches. The current study looked at the effects of black cumin-enriched acha-based cookies on antioxidant and cholinesterases [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] activities in the brain of high-fat/streptozotocin-induced type-2 diabetic mice infected with Plasmodium bergei. The mice were infected with Plasmodium berghei (NK65 strain) after receiving STZ (50 mg/kg b.w.) intraperitoneally to cause diabetes and high blood glucose levels of > 200 mg/dL. Then, as a treatment, the acha-based cookies enriched with black cumin were administered to the experimental mice. The effect of the cookies on neuronal cholinesterases (AChE and BChE) activities, reactive oxygen species (ROS), thiobarbituric acid reactive species (TBARS), and reduced glutathione (GSH) levels, as well as neuronal antioxidant [superoxide dismutase (SOD), catalase, glutathione-s-transferase (GST), and glutathione peroxidase (GPx)] were assessed. The outcome revealed a (P < 0.05) rise in cholinesterases and MAO activities, ROS, and TBARS levels, with a concomitant decrease in neuronal antioxidant enzymes and GSH levels in the P. bergei-infected diabetic mice. However, the consumption of black cumin-enriched acha-based cookies by the mice caused an improved antioxidant status and significantly decreased the activities of AChE, BChE, and MAO activities and ROS and TBARS levels. The neuroprotective potential of the cookies, in particular, in the treatment of neurochemical deficit in P. bergei-infected diabetic mice was confirmed.