The 17th-ranked Russian won 7-6(12), 6-4 to claim a sixth career title against Mensik, the youngest finalist at a tour event since Carlos Alcaraz at Umag in 2021.
"Every title is a special one," Khachanov, who didn't drop a set all week, said on court.
"Every time, you want to win. We play around 22 tournaments per season and at the end of the day, you compete every week. For sure here in Doha it is one of the nicest trophies."
Czech teenager Mensik, ranked 116 who will break into the top 100 next week, was playing in just his third main draw event following breakout runs to the third round of the 2023 US Open and a second-round appearance at the Australian Open last month.
On his way to the Doha final, he knocked out former world number one Andy Murray as well as top seed Andrey Rublev.
He had his chances in a marathon opener on Saturday when his Russian opponent saved four set points.
"I thought yesterday's tie-break was preparation for today," added Khachanov who had claimed a 14/12 breaker against Alexei Popyrin on Friday in the semi-finals.
"Today I couldn't believe it was the same score, same tie-break... I stayed strong, I'm extremely happy that I won the first set. It lifted me a lot and gave me a lot of confidence to step up in the second."
Khachanov also faced down 16 aces from the young Czech.
"For a minute, I thought I was playing John Isner and not Jakub Mensik today," said the Russian.
