The orchestration of cells to form and maintain larger structures is a complex and dynamic process reiterated throughout organismal development. Connective extracellular matrix (ECM) provides structural integrity and flexibility to allow for stresses associated with movement and mechanical force transmission in epithelial and muscle tissues. In Drosophila, perturbation of ECM results in weakened or malformed muscle attachment sites (MASs) that detach, making the MAS an excellent model for studying this phenomenon. We have identified a new role for a secreted hemolymph protein called Fondue (Fon) in Drosophila muscle attachment. Previous studies of Fon focused on its role in clot stability and innate immune response. However, early pupal lethality and abnormal pupal morphology in unchallenged individuals indicated that Fon had a developmental role. Transgenic flies containing a tagged Fon construct revealed that Fon-GFP accumulates at both indirect and direct attachment sites in L3 larvae. Both fon mutants and fon RNAi fillets contained body wall muscles that detach with large gaps between subsets of muscles across hemisegments. Using TEM to analyze MAS ultrastructure, we found that fon mutants had disrupted cuticle and tendon architectures, a lack of muscle-tendon interdigitation, and a loss of electron-dense matrix accumulation. Together, the TEM data and abnormal muscle morphologies observed in L3 fillets indicate that Fon is a critical regulator of ECM organization and overall MAS integrity. In a fon mutant sensitized background, we identified both tig and tsp as candidate interactors of Fon at the MAS. RNAi knockdown of either transcript increased detachment phenotypes compared to fon heterozygotes or candidate RNAi fillets alone. Tig has also been identified as a component of the hemolymph clot. We were able to identify one other secreted hemolymph protein, Lsp1γ, that results in muscle detachment upon RNAi knockdown. Using an Lsp1γ-GFP construct, we observed Lsp1γ-GFP localizing in a tendon-associated pattern at the MAS. From this data we can conclude that the analogous structures of the hemolymph clot and the muscle attachment site require a unique and overlapping set of secreted proteins in Drosophila melanogaster, identifying a connection between innate immune and muscle development processes.