This study explores the potential strategic determinants of firm performance, with an emphasis on R&D investment and operational efficiency in leading U.S. manufacturing firms. In particular, it investigates R&D as a driver of technological innovation, and operational efficiency and as an indicator of the best- practice operations, for their impact relative to Tobin’s Q and Market value. The study jointly uses ordi- nary least square multiple regression (OLSMR) and backpropagation neural network (BPNN), not only to measure the statistical significance of factors, but also to explore new insights into their relative impor- tance, and to determine the differential impact of each factor following the varying performance levels. A major finding is that proactive R&D investments and operational excellence are the most impactful factors on both metrics of performance as compared to other conventional factors used in this study. Another encouraging finding is that both R&D intensity and operational efficiency are even more influen- tial in the above-average performers and yield higher returns in market valuation. Through a combined OLSMR-BPNN approach, this study presents insightful findings on this intriguing subject and highlights prospective research opportunities.