Haloperidol decanoate (HD) has been implicated in cognitive impairment. Agomelatine (AGO) has been claimed to improve cognition. We aimed at investigating the effects of HD + low- or high-dose AGO on cognition, verifying the melatonergic/dopaminergic to the cholinergic hypothesis of cognition and exploring relevant cardiovascular issues in adult male Wistar albino rats. HD + high-dose AGO prolonged the step-through latency by + 61.47% ( P < 0.0001), increased the time spent in bright light by + 439.49% ( P < 0.0001), reduced the time spent in dim light by -66.25% ( P < 0.0001), and increased the percent of alternations by + 71.25% ( P < 0.0001), despite the reductions in brain acetylcholine level by -10.67% ( P < 0.0001). Neurodegeneration was minimal, while the mean power frequency of the source wave was reduced by -23.39% ( P < 0.05). Concurrently, the relative expression of brain melatonin type 2 receptors was reduced by -18.75% ( P < 0.05), against increased expressions of dopamine type 5 receptors by + 22.22% ( P < 0.0001) and angiopoietin-like 4 by + 119.18% ( P < 0.0001). Meanwhile, electrocardiogram (ECG) demonstrated inverted P wave, reduced P wave duration by -36.15% ( P < 0.0001) and PR interval by -19.91% ( P < 0.0001), prolonged RR interval by + 27.97% ( P < 0.05), increased R wave amplitude by + 523.15% ( P < 0.0001), and a depressed ST segment and inverted T wave. In rats administered AGO, HD, or HD + low-dose AGO, Alzheimer's disease (AD)-like neuropathologic features were more evident, accompanied by extensive ECG and neurochemical alterations. HD + high-dose AGO enhances cognition but alters cardiac electrophysiology. SIGNIFICANCE STATEMENT Given the issue of cognitive impairment associated with HD and the claimed cognitive-enhancing activity of AGO, combined high-dose AGO with HD improved cognition of adult male rats, who exhibited minimal neurodegenerative changes. HD + high-dose AGO was relatively safe regarding triggering epileptogenesis, while it altered cardiac electrophysiology. In the presence of low acetylcholine, the melatonergic/dopaminergic hypothesis, added to angiopoietin-like 4 and Kruppel-like factor 9, could offer some clue, thus offering novel targets for pharmacologic manipulation of cognition.