Introduction. Irrational prescribing is a major cause for irrational drug use. Bad prescribing habits lead to ineffective and unsafe treatment, exacerbation or prolongation of illness, distress and harm to the patient, and higher costs. Incidence of irrational prescribing practice cannot be reduced without a critical intervention by assessing the causes. Objectives. The objective of this study was to assess drug prescription pattern, using WHO prescribing indicators, in OPD at Mekelle General Hospital (MGH) Methodology. The study was conducted at Mekelle General Hospital (MGH), Mekelle, Northern Ethiopia, from December 2016 to April 2017. A descriptive cross-sectional, retrospective hospital-based study design was used to assess prescriptions at OPD in MGH from 01 January to 31 December 2016. A systematic random sampling technique was used to select prescriptions at the time of data collection. Result. 384 prescriptions were analyzed. 751 medications were prescribed from which 679 (90.4%) were with their generic name, 225 (58.6%) prescriptions contained antibiotics, 162 (42.2%) prescriptions were encountered with injection, and 648 (86.3%) encountered from the hospital list of medicine. Conclusion. In general, average number of drugs per encounter, generic prescribing, and the use of EDL/formulary of the hospital to prescribe drugs reviewed in this study were totally out of the recommended values and hence inappropriate. The study also revealed overprescribing of both antibiotics and injections.