The Pasadena institution, familiarly known as Caltech, retained its ranking as the world's best research university in the 2012-13 World University Rankings released this week by the Times Higher Education magazine.
The University of Oxford and Stanford University were tied for second place while Harvard, last year's runner-up, placed fourth.
The rest of the top-ranked schools in order were: Massachusetts Institute of Technology, Princeton University, University of Cambridge, Imperial College London, UC Berkeley and the University of Chicago.
University of California campuses at Berkeley and Los Angeles managed to maintain their top 20 positions despite massive state funding cuts to higher education, the Los Angeles Times reported.
Times Higher Education created its rankings based on research funding, faculty publication, research citations, the international makeup of faculty and students and the number of doctorates awarded.
Caltech President Jean-Lou Chameau credited the success of the school, home to NASA's Jet Propulsion Laboratory, to a simple philosophy.
"We always try to recruit exceptional faculty and exceptional students," Chameau told the Times. "We try to support them the best we can and we encourage them to look at big questions, important scientific issues. It has resulted in game-changing types of discoveries."