The 83 all out stands as the lowest total recorded by a full member against an associate side. Nepal's 90-run victory also marks the largest winning margin an associate has achieved over a full member.
"We are very happy," Nepal captain Rohit Paudel said.
"It took a lot to win against a Test-playing country.
"This was a very important series for us to showcase our cricket and talent to the world. The way we've been playing the last two or three years, lots of eyes are on us. The motivation is to complete a clean sweep."
Nepal, facing a full member nation in a T20 series for the first time, stunned the two-time world champions by clinching the three-match contest with a game to spare as they also won by 19 runs in the opener.
They made 6-172 in Sharjah on Monday with opener Aasif Sheikh anchoring the innings with an unbeaten 68 off 47 balls. Sundeep Jora scored 63 off 39 as Nepal recovered from 2-14 and 3-43 to post a challenging total.
West Indies began badly, losing their first two wickets for five runs off 20 balls, and never recovered. Jason Holder top-scored with 21 while only Ackeem Auguste (17) and Amir Jangoo (16) also made double figures.
The last five wickets fell for nine runs with Aadil Ansari taking 4-24 and Kushal Bhurtel 3-16.
"For us, it's just about understanding really fast that this is international cricket," West Indies captain Akeal Hosein said.
"If you try to benchmark yourself here and can't match the level, then you need to look in the mirror and ask yourself if you're really international material."
The series will conclude on Tuesday.
With The AP.
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