Inadequate pain management affects the patient outcome. Pain assessment and management are fundamental in nursing care, and nurses must be equipped with adequate knowledge and a positive attitude toward pain assessment and management. This study aims to evaluate nurses’ knowledge and attitudes regarding pain assessment and management at King Fahad Hospital, Al-Madinah, Kingdom of Saudi Arabia. A quantitative, cross-sectional survey, using a self-administered questionnaire, was conducted from January to February 2020 with 660 registered nurses working in the Emergency Department, critical care units, inpatient and outpatient departments at King Fahad Hospital in Al-Medinah, Kingdom of Saudi Arabia. The data were analyzed with descriptive and inferential statistics. Of the 660 nurses, 291 responded, resulting in a response rate of 44.09%. The participants’ scores ranged from 17.7% to 100%, with a mean score 45.29%. The majority of the participants (70.1%) had a poor level of knowledge and attitudes (score < 50%). Nurses working in the outpatient department scored significantly higher than the group working in the Emergency Department and inpatient wards. Deficient knowledge and negative attitudes were found and nurses continue to underassess and undertreat pain. Nursing school curricula and in-service continuous education must equip nurses with the required knowledge and attitudes to enable them to manage pain effectively.