Organophosphorus (OP) compounds are extensively used in widespread applications, causing considerable poisonings around the world. Current treatments against poisoning by organophosphates, nerve agents, or other acetylcholinesterase (AChE) inhibitors are based on the intravenous or intramuscular administration of a muscarinic antagonist (atropine), a cholinesterase reactivator (an oxime), and an anticonvulsant (a benzodiazepine like diazepam). Since these antidotes have serious adverse effects, the prophylaxis against OP intoxication is based principally on the administration of reversible cholinesterase inhibitors. However, evidence demonstrates that, in addition to the AChE inhibition, the toxicity of OP compounds is mediated by the generation of nitric oxide and other free radicals. These toxic molecules can be counteracted by antioxidants such as vitamins C and E, spin traps, melatonin, and low-molecular-weight thiols. The latter compounds can also increase the synthesis of glutathione, which can both ameliorate the OP-induced oxidative stress and enhance OP detoxification. Therefore, the low side effects of antioxidants make them suitable for pretreatment against a potential OP poisoning and might be used in combination with the standard treatments. The present review focuses on how OP compounds cause oxidative stress, apoptosis, and necrosis; how cells respond to these processes; and how antioxidants can improve OP poisoning.