Aim and background: The teaching strategy, self-directed learning (SDL), is a very important and effective method used for teaching and learning that enables medical students for lifelong learning, enabling them to fulfill their learning requirements in self-directing way, identify ideal learning resources, identify objectives ideal for learning, and also assess the process involved in learning all through their career. The objectives of the present study were to compare the effectiveness of SDL alone and SDL blended with lecture and to study the perceptions of students about SDL as a TL method. Methodology: A prospective observational study was conducted involving a total of 180 phase I MBBS students who gave voluntary consent for the study. Study protocol consisted of two sessions: Session 1: SDL alone, and Session 2: Lecture following SDL. A baseline pretest was conducted, and posttest was conducted after the completion of both sessions using a validated multiple-choice questionnaire, and students’ perception forms were analyzed. Results: There was a statistically significant increase in posttest scores compared to the baseline pretest scores, and further, there was a statistically significant increase in posttest scores of lectures following SDL sessions compared to posttest scores of an SDL session. Conclusion: Overall performance of the students was improved when a topic was taken as SDL followed by didactic lecture, which has been indicative of an improvement in learning outcomes when adopting the SDL module. Our study strongly recommends a sensible combination of SDL and lecture, rather than implementation of SDL alone, for phase one MBBS students. Clinical significance: Blended learning SDL combined with lecture has better outcomes as it enables the students to clinically correlate the topic learned in biochemistry.