Greipel's victory was a surprise to the rest of the peloton after the German crossed the line on his own, 14 seconds ahead of the rest of the field.
Greg Henderson attacked for Lotto-Belisol with 40km to go and no one was able to stay with him until his team-mate Greipel caught up with him with just two laps of the 5.5km finishing circuit to go.
Henderson powered Greipel to the foot of the Pabeierbierg climb where the sprinter rode past his team-mate to cross the line in first place.
Greipel was pleased with his performance as it was a different type of victory and hopes he can continue to ride well in the Tour de France.
According to Cycling News, Greipel said: “This is of course a special victory because I reached the finish solo, but for me this is also a step towards the Tour de France. I am confident and the condition is well.
“This victory is something different than normal. It’s the first time in my pro career that I won solo.
“We really wanted to have someone in the break today because there was a chance it would make it in this last stage.”
The 31-year old-praised Henderson for his work but admits he found it hard out the end.
“Tactically we rode a really good final together. I had cramps at the end so it wasn't easy on that steep climb. I had to go really hard there."
Henderson believes he knew Greipel would be able to catch him in the break but wouldn't recommend leading a fellow rider out for that long.
"I attacked the break early because I felt everyone was getting tired. I knew André would be able to sit on for some 30 kilometres in the group.
"He waited and then attacked the break. He reached me and I went full gas for one more lap with him sitting on my wheel.
"I opened some more time on the chasers and then sent Andre on his way. It was the longest lead-out I ever did in my career. And I wouldn't recommend it to anyone," he said.
The overall victory of the Tour of Luxembourg went to Matti Breschel of Tinkoff-Saxo after finishing with a combined time of 17 hours 59 minutes and four seconds.
1André Greipel (Ger) Lotto Belisol4:04:54
2Matti Breschel (Den) Tinkoff-Saxo0:00:14
3Daniel Teklehaimanot (Eri) MTN - Qhubeka
4Rudy Molard (Fra) Cofidis, Solutions Credits
5Silvio Herklotz (Ger) Team Stölting
6Björn Leukemans (Bel) Wanty - Groupe Gobert
7Michael Morkov (Den) Tinkoff-Saxo
8Frank Schleck (Lux) Trek Factory Racing
9Sergey Lagutin (Rus) Rusvelo
10Laurent Evrard (Bel) Wallonie - Bruxelles
1Matti Breschel (Den) Tinkoff-Saxo17:59:04
2Jean-Pierre Drucker (Lux) Wanty - Groupe Gobert0:00:19
3Michael Morkov (Den) Tinkoff-Saxo0:00:20
4Rudy Molard (Fra) Cofidis, Solutions Credits0:00:21
5Sergey Lagutin (Rus) Rusvelo0:00:26
6Silvio Herklotz (Ger) Team Stölting0:00:35
7Romain Hardy (Fra) Cofidis, Solutions Credits0:00:43
8Laurent Evrard (Bel) Wallonie - Bruxelles0:00:48
9Frank Schleck (Lux) Trek Factory Racing0:00:56
10Björn Leukemans (Bel) Wanty - Groupe Gobert0:01:01
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