The under-treatment of pain is the most disturbing and annoying symptom for hospitalized patients worldwide, yet it is poorly assessed and managed. Pain undermines a person’s quality of life and negatively affects their physical, emotional and spiritual wellbeing. Nurses have a vital role in implementing pain management effectively; therefore inadequate knowledge remains a major barrier to achieving effective pain management. This study aims to assess knowledge levels and attitudes regarding pain management among nurses working in hospitals in south of Palestine. A quantitative cross-sectional study design was utilized to recruit a proportionate sample of 380 staff nurses working in different wards in six governmental and private hospitals in Palestine. A modified Arabic version of Nurses’ Knowledge and Attitude Survey questionnaire regarding Pain was used to answer the research questions. The results of the study showed that a mean score of knowledge was 15.5 out of34 (45.6% out of 100%).This finding indicates that staff nurses had deficit in knowledge and negative attitudes toward pain assessment and management. The findings showed no significant difference in the mean score of knowledge in relation with gender (p = 0.181), age-group (p = 0.399), level of education (p = 0.934), and previous training courses or workshops on pain management (p = 0.612), except for the place of work (p <0.001).The results of this study indicate that there are serious challenges to adequate pain management. Curricular evaluation and/or change aiming to promote pain management and correcting the ingrained misconceptions are needed.