In late May, the president had named Mohammad Masoom Stanekzai, a top official in the government body overseeing the country's peace process, to head the ministry.
Stanekzai needed 107 votes from MPs to be approved, but received just 84 out of the 213 who cast votes, dragging out the process of finding a candidate for the post into its 10th month.
"Masoom Stanekzai unfortunately could not get the vote of confidence from the lower house of parliament," the speaker of the lower house, Abdul Rauf Ibrahimi, told today's session.
Ghani's previous pick for the post, former Afghan army chief of staff Sher Mohammad Karimi, was also rejected by the lower house in January.
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The repeated delay on the appointment is reportedly due to differences between Ghani and his chief executive and former presidential election rival, Abdullah Abdullah, over their choice of candidate, with many linking the leadership vacuum to a recent uptick in deadly insurgent attacks.
The empty post has stoked fears of instability in the troubled nation after NATO troops pulled back from the frontlines in December last year after 13 years of conflict against the Taliban.
A NATO combat mission formally ended in December but a small follow-up foreign force of about 12,500 mainly US troops has stayed on to train and support local security personnel.
The Taliban, bolstered by battle-hardened Central Asian fighters in their ranks, recently captured the district headquarters of Chardarah, adjoining Kunduz city, triggering fears they would overrun their first provincial capital since the 2001 US invasion of Afghanistan.
The defence post is not the only one with which Ghani has had trouble: in April, Afghanistan's parliament approved 16 Cabinet nominees -- including four women -- but only after months of delays.