After graduation, he worked as a postdoctoral fellow at Harvard University with Paul Zamecnik, who was then one of a very small number of researchers studying the biochemistry of protein synthesis.
Siekevtiz's work elucidated the role of mitochondria in generating adenosine triphosphate (ATP) required for protein synthesis, which led him to become interested in general matters of energy metabolism.
[3] Throughout his independent faculty career, Siekevitz continued to collaborate closely with Palade, and the two had a number of co-supervised students and postdoctoral fellows, including David D. Sabatini and Günter Blobel.
Beginning in the 1970s, Siekevitz invested significant research effort in studying the synapse and the protein composition of the postsynaptic density.
Siekevitz enjoyed playing the piano and writing fiction – he published two novellas during his lifetime and left several unpublished short stories after his death.