Aim and objectives: To examine the factors that influence nursing students��� mathematics self-efficacy, the effect of numeracy instruction on self-efficacy, and the association between self-efficacy and numeracy test performance. Background: Medication administration errors, including administering incorrect dosages or infusion rates, can result in serious harm to patients. Hence, it is essential that nursing students are adequately prepared with the necessary numeracy skills during their nursing program. Design: This quasi-experimental cohort study used a pre- and post-test survey design. The study complied with the STROBE checklist for cohort research. Methods: In total, n = 715 undergraduate first year nursing students participated in the study from June to October 2017 at a single multi-campus university in the Western Sydney region of Australia. Data were collected at three time-points: (a) baseline, including assessing pre-instruction mathematics self-efficacy (NSE-Math scale); (b) 6-week follow-up; including assessing post-instruction mathematics self-efficacy; and (c) numeracy test performance was collected at 7-week follow-up. Findings: At baseline, those with high NSE-Math scale scores were more likely to be male and have at least high school advanced mathematics level education. Following structured numeracy instruction, NSE-Math scale scores increased significantly, and those who obtained a satisfactory grade in their numeracy assessment were more likely to have high NSE-Math scale scores and high academic performance in the previous semester. Conclusion: The study shows that structured numeracy instruction improved mathematics self-efficacy, which in turn influenced numeracy test performance. Relevance to clinical practice: Using a structured medication numeracy pedagogical approach, to teach skills in nursing undergraduate programs, provides students with the foundations to improve mathematics self-efficacy and to be successful and safe with medication numeracy calculations and administration in clinical practice.