Topoisomerase 3b (TOP3B)-TDRD3 is a dual-activity topoisomerase complex in animals that can change topology for both DNA and RNA. A current hypothesis proposes that this complex interacts with Fragile X mental retardation protein, FMRP, to regulate mRNA translation. Here we examined this hypothesis by identifying TOP3B-TDRD3-bound mRNAs in human HCT116 cells; and analyzing the effect of inactivating TOP3B, TOP3B catalytic activity, TDRD3, and FMRP, on translation and abundance of these mRNAs. We found that TOP3B-TDRD3 resembles FMRP in preferentially binding to coding regions of long mRNAs. Complete inactivation of TOP3B protein, but not a point mutation that only disrupts TOP3B catalytic activity, preferentially reduced the abundance of the TOP3B-TDRD3-bound mRNAs. Moreover, ablation of the complex or inactivation of TOP3B catalytic activity alters translation for some but not all TOP3B-TDRD3 bound mRNAs, suggesting that TOP3B-TDRD3 may solve topological problems for specific mRNAs. Finally, several schizophrenia and autism-risk genes are bound and regulated by TOP3B-TDRD3 in mRNA translation and abundance by topoisomerase activity dependent and independent manners. Our data suggest that TOP3B-TDRD3 can regulate mRNA translation and abundance by topoisomerase activity dependent or independent mechanisms; and disruption of this function could contribute to pathogenesis of psychiatric disorders in TOP3B mutation carriers.