The physical basis of noncovalent interactions (PBI) represents a foundational concept in biochemistry education that students consistently struggle to grasp. Due to the difficulty of PBI, there is a need to determine the optimal instructional approach for presenting the concept in a classroom setting. Three evidence‐based pedagogies have been proposed to enhance student learning compared to traditional lecture‐based lessons: productive failure, worked examples plus practice, and guided inquiry. The productive failure approach is based upon achieving a desirable level of difficulty and preparing students for future learning. Students first attempt to solve problems independently and afterward receive direct instruction on the correct procedures and concepts to solve the problems correctly. The worked examples plus practice approach is based upon reducing cognitive load. Students first receive instruction on how to solve a problem correctly. Then they attempt to solve similar problems independently. The guided inquiry approach is less well‐defined but generally involves instructors continuously and actively supporting students during problem solving. These approaches have never been directly compared. We investigated the impact of productive failure, worked examples plus practice, and two forms of guided inquiry: scaffolded and unscaffolded guidance on student learning of PBI. We collected data from 123 students in Fall 2018 and 66 students in Spring 2019. Students took a basic knowledge pre‐test, and we then randomly assigned them to one of the four experimental conditions. After the lesson, they took a basic knowledge posttest and completed a series of near and far transfer constructed‐response problems. Near transfer problems are problems that resemble the problems used during instruction, while far transfer problems draw upon the same knowledge learned in the lesson but are presented in a different context. After analytically coding and scoring student responses, we found no significant effect of instruction type on basic knowledge change, indicating that students learned basic aspects of PBI in all conditions. We found that unscaffolded guidance was not sufficient for near transfer problem‐solving. Students in all other instruction types performed better on near transfer problems than students in unscaffolded guidance. For far‐transfer problem solving, we found no significant difference between productive failure and scaffolded guidance. These findings suggest important implications for optimizing student learning of PBI in undergraduate biochemistry. Biochemistry instructors need to offer more than unscaffolded guidance to maximize student learning of PBI, and productive failure or scaffolded guidance may facilitate the knowledge transfer indicative of deeper conceptual understanding.Support or Funding InformationThis material is based upon work supported by the National Science Foundation under Grant No. DRL1350345. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.