The goal of the current study was to investigate the effects of an immersive virtual reality (IVR) science simulation on learning in a higher educational setting, and to assess whether using self-explanation has benefits for knowledge gain. A sample of 79 undergraduate biology students (40 females, 37 males, 2 non-binary) learned about next-generation sequencing using an IVR simulation that lasted approximately 45 min. Students were randomly assigned to one of two instructional conditions: self-explanation (n = 41) or control (n = 38). The self-explanation group engaged in a 10 min written self-explanation task after the IVR biology lesson, while the control group rested. The results revealed that the IVR simulation led to a significant increase in knowledge from the pre- to post-test (ß_Posterior = 3.29). There were no differences between the self-explanation and control groups on knowledge gain, procedural, or conceptual transfer. Finally, the results indicate that the self-explanation group reported significantly higher intrinsic cognitive load (ß_Posterior =.35), and extraneous cognitive load (ß_Posterior =.37), and significantly lower germane load (ß_Posterior = −.38) than the control group. The results suggest that the IVR lesson was effective for learning, but adding a written self-explanation task did not increase learning after a long IVR lesson.