Background Opioid use and opioid use-related problems contribute significantly to increased morbidity rates and premature deaths as well as an increased economic burden. Nurses have key roles in providing care to this patient population; however, they often report low motivation toward working with these patients. Examining personal and professional attitudes associated with nurses’ motivation to work with this population can present a valuable opportunity to enhance their willingness to intervene at an earlier stage when patients do not have a diagnosable opioid use disorder. Methods A descriptive, correlational design was used. Nurses were recruited from four hospital settings in Southwestern Pennsylvania. Data on nurses’ demographic/background characteristics, personal attitudes, professional attitudes, and motivation related to working with patients with opioid use and opioid use-related problems were collected via a paper/pencil survey and analyzed using linear regression. Results A sample of 234 nurses were included in the final analyses. Personal attitudes associated with nurses’ motivation included personal experience with a family member related to alcohol and/or other drugs, and stigma perceptions (familiarity, perceived dangerousness, fear, social distance and personal responsibility beliefs). Professional attitudes associated with nurses’ motivation included working experience with substance use (SU), SU education as continuing education or other educational resources, role security, therapeutic commitment, role responsibility, and self-efficacy. Conclusions This study's findings provide valuable information regarding the bivariate relationships between nurses’ personal attitudes, professional attitudes, and motivation to work with patients with opioid use and opioid use-related problems. The study provides a base for future studies aimed at developing interventions to enhance nurses’ motivation to work with this patient population particularly related to preventing the progression of opioid use to a diagnosable disorder.