Diphenhydramine (DPH) was used to treat a number of conditions including allergic symptoms and itchiness, common cold, insomnia, motion sickness, and extrapyramidal symptoms, are associated with some adverse effects such as dry mouth and throat, increased heart rate, pupil dilation, urinary retention and etc. This study aims to evaluate hydrogel drug delivery of DPH by tree gelling agents. Carboxy methyl cellulose (CMC), Hydroxy propyl methyl cellulose (HPMC) and methyl cellulose (MC) in the presence of 1 and 2% of DPH. All gel samples were evaluated for physical appearance, drug release and stability for the period of two months. Drug release studies were done by Franz diffusion cell. This in vitro study demonstrates the advantages of gelling polymers in transdermal drug delivery applications. The ability of molecules to diffuse into (drug loading) and out of (drug release) a hydrogel enables to use this system for drug delivery. DPH gel formulations prepared with different gelling agents HPMC, CMC and MC showed acceptable physical properties and drug release study. Among all gel formulations, MC gels revealed superior physical properties and drug release. The result obtained suggests the feasibility of designing transdermal delivery systems for DPH successful and effective besides overcoming the drawbacks of oral administration.