This paper provides a novel instructional methodology that is designed to conceptually address the four main challenges faced by 21st century students, who must learn in a multitude of educational settings (face to face, hybrid and online). The online learning neuroscience supported instructional methodology detailed in this article also provides an active solution that when implemented addresses the needs of Colleges and Universities who desire new methods to achieve their academic goal (such as increase student retention and graduation rates, and respond to their high standards of academic rigor) (Osler & Wright, 2016). The use of the "E-Learning Trioengineering" also adds value to informative investigative inquiry through the efficacy of digital instruments and tools via eduscientifically-engineered (Osler, 2013a) research designs (Osler, 2015a). Additional research into "E-Learning Trioengineered" online solutions will further advance learning, and conversely, learning solutions that are much needed in digital classrooms.