Student populations are diverse such that different types of learners struggle with traditional didactic instruction. Problem-based learning has existed for several decades, but there is still controversy regarding the optimal mode of instruction to ensure success at all levels of students' past achievement. The present study addressed this problem by dividing students into the following three instructional groups for an upper-level course in animal physiology: traditional lecture-style instruction (LI), guided problem-based instruction (GPBI), and open problem-based instruction (OPBI). Student performance was measured by three summative assessments consisting of 50% multiple-choice questions and 50% short-answer questions as well as a final overall course assessment. The present study also examined how students of different academic achievement histories performed under each instructional method. When student achievement levels were not considered, the effects of instructional methods on student outcomes were modest; OPBI students performed moderately better on short-answer exam questions than both LI and GPBI groups. High-achieving students showed no difference in performance for any of the instructional methods on any metric examined. In students with low-achieving academic histories, OPBI students largely outperformed LI students on all metrics (short-answer exam: P < 0.05, d = 1.865; multiple-choice question exam: P < 0.05, d = 1.166; and final score: P < 0.05, d = 1.265). They also outperformed GPBI students on short-answer exam questions (P < 0.05, d = 1.109) but not multiple-choice exam questions (P = 0.071, d = 0.716) or final course outcome (P = 0.328, d = 0.513). These findings strongly suggest that typically low-achieving students perform at a higher level under OPBI as long as the proper support systems (formative assessment and scaffolding) are provided to encourage student success.