US-India strategic partnership in the volatile region of South Asia is a complex phenomenon. Prior to World War – II, there had no significance of South Asia in the eyes of US, but now the importance strategic of the region has changed drastically. The region is now well equipped with nuclear weapons and missiles as well as by regional proxies as non-state actors with intensified terrorism on high profile. Pakistan, Afghanistan and India are at the centre stage of all these activities. This article explores how the US changed its strategic priorities in the South Asian region with changing sequences and its partners with the change of time gradually and got concrete shape between 2000 - 2016. This partnership saga that was sparked late in Clinton administration (1993-2001) and carried out fully during the Bush administration (2001-2008), as well as has been retained by the Obama administration (2009-2016) as significant part of Pivot to Asia (2011) and got the attention in recent renewal of the Mutual Defense Framework (2015) between Barack Obama and Narendera Modi.