Abstract Objective To implement and evaluate a problem-based learning (PBL) pain and palliative care elective course to develop studentsʼ pain and symptom management pharmacotherapy knowledge, clinical reasoning process, and self-directed learning skills. Methods Each week students received a patient case to independently develop an assessment and plan for each pain and symptom management problem. During class the students discussed their findings within small groups in preparation for a large-group discussion with the instructor. Studentsʼ course grades were based on weekly pre-class case preparation, individual case studies, and self-reflection questions. To assess knowledge gained over the semester a free-response pre- and post-course test was given. Results Twenty-five students enrolled in this course. A t-test comparison of the pre- and post-tests yielded a significant difference between the pre- and post-test scores (p < 0.001), with the mean score for the tests increasing from 9.6 (out of 20 points) on the pre-test to 14.1 on the post-test. Pearsonʼs correlation coefficient between the pre- and post-test was 0.45, indicating increased scores were not a result of improvement only among the strong students. The normalized gain was 0.43. The average score for each individual case study was slightly more than 80%. Four themes were noted in the studentsʼ self-reflections including patient/family goals of care, individualization of patient care and contrast to curative treatment, improved comfort with “gray therapeutic areas,” and advantages and disadvantages of problem-based learning. Conclusions Students demonstrated improved pain and symptom management pharmacotherapy knowledge, clinical reasoning process, and self-directed learning skills after course completion. The skills developed by students will benefit them in future clinical practice. Additional studies are needed to assess the long-term impact of the skills developed in this course.