Baculovirus infection boosts the host biosyntheticactivity towards the production of viral componentsand the recombinant protein of interest, hyper-productivephenotypes being the result of a successful adaptation of thecellular network to that scenario. Spodoptera frugiperda derivedSf9 and Trichoplusia ni derived High Five cell lines have a majortrack record for the production of recombinant proteins, withHigh Five cells presenting higher productivities. A metabolicprofiling of the two insect cell lines was pursued to underpinspecific cellular traits behind productive phenotypes. Multivariateanalysis identified cell-line dependent metabolicsignatures linked to productivity. Pathway analysis highlightedcellular pathways of paramount importance in supportinginfection and protein production. Moreover, better producerphenotypes proved to be correlated with the capacity of cellsto shift their metabolism in favor of energy-generatingpathways to fuel biosynthesis, a scenario observed in the HighFive cell line. Metabolomic profiling allowed us to identifymetabolic pathways involved in infection and recombinantprotein production, which can be selected as targets forfurther improvement of the system.