Nematodes undergone a remarkable expansion of nuclear receptor (NR) with C. elegans harbouring 284 NR genes. One of the most studied nematode NR is DAF-12, which controls the decision to enter dauer diapause, an alternative quiescent larval 3 stage (L3d) only established upon harsh conditions such as crowding, food deprivation or high temperature. Exit from the L3d is determined by the presence or absence of DAF-12 ligands, such as Δ4-and Δ7-dafachronic acids (Δ4-and Δ7-DA). DAF-12 also contributes to trigger development to adulthood in several nematode parasites which enter their definitive host at the developmentally arrested infectious larval stage (iL3). However, whether DAF-12 is functioning similarly in different parasitic nematode clade is not clear. Here, we characterized DAF-12 from the filarial nematodes Brugia malayi and Dirofilaria immitis and compared them with DAF-12 from the non-filarial nematodes Haemonchus contortus and Caenorhabditis elegans. Interestingly, Dim and BmaDAF-12 share a striking higher sensitivity than Hco and CelDAF-12 to Δ4-and Δ7-DA. Modelling of DimDAF-12 ligand binding domain revealed that several residues confer high-affinity binding of DAs. Moreover, sera from different mammalian species activated specifically Dim and BmaDAF-12 while the hormone-depleted sera failed to activate the filarial DAF-12. Importantly, Δ4-DA has been quantified in human and mouse serum. Consistent with these observations, we showed that spiking hormone-depleted mouse serum with Δ4-DA at the concentration measured in normal mouse serum restores its capacity to activate DimDAF-12. Accordingly, hormone-depleted serum delayed D. immitis iL3 development in vitro compared to normal serum. Altogether, our data suggest that filarial daf-12 may have evolved in filarial parasites to sense the host environment through their ligands and to promptly trigger parasite growth upon infection. This work sheds new light on NR evolution in nematodes and may open the route to novel therapies to treat filarial infections.