The biggest difference between Benadryl vs. Zyrtec is that Benadryl is a first-generation antihistamine, meaning is more likely to make your dogs drowsy and have more side effects than Zyrtec, a second-gen antihistamine. Research shows that oral cetirizine effectively prevented cutaneous allergic reactions without any obvious adverse effects in dogs. In contrast, oral Diphenhydramine (the active ingredient in Benadryl) failed to show an inhibitory effect.[8]