The three-time runner-up had looked impressive in his first two matches but was outplayed in every department by Lopez, who hit 57 winners and made only seven unforced errors in a 7-6 (7/2) 7-6 (7/2) 6-4 victory.
Greg Rusedski, Andy Murray and Roger Federer, who did it twice, are the only other players to have denied Roddick a set at the All England Club.
Despite the disappointment of being sent home, the American had few regrets in comparison to last year, when he was surprisingly beaten in the fourth round by Lu Yen-hsun.
He said: “This year’s a lot easier to deal with than last year, where I felt like I gave it away. I got beat. He came out, he served about as well as someone has.
“The stuff that’s enabled me to beat him seven times, making passing shots under duress, making him play defence on his forehand, he did well today. He mixed up his serve. There weren’t a whole lot of patterns. He played an outstanding match.”
Roddick looked back to his best when he reached the Wimbledon final in 2009 and pushed Roger Federer, who had beaten him in 2004 and 2005, all the way to 16-14 in the fifth set.
Asked if it crosses his mind that he may never win Wimbledon, the 28-year-old replied: “I’m human. Of course it does. But you keep moving forward until you decide to stop.
“At this point I’ve not decided to stop so I will keep moving forward.
“I haven’t played well this year, for sure. I don’t think I’ve played my best since probably April of last year. I think I can. I’ve been up against some stuff. But it has to get better. There’s no doubt.”
Lopez, a two-time Wimbledon quarter-finalist, had never beaten Roddick in seven previous meetings but he took heart from a close match at Queen’s Club two weeks ago and he declared today’s victory to be his best at grand slams.
The 29-year-old said: “It’s definitely a great win for me. I’ve beaten a couple of great players at Wimbledon in the last 10 years but to beat Andy on this court is very special.
“I would say maybe the best probably.”
Defending Wimbledon champion Rafael Nadal must return today to continue his bid to reach the fourth round after his clash with Gilles Muller was affected by the weather.
The world No 1 had just taken a nervy first set on a tie-break on Court One when the heavens opened at 5.40pm, with play officially called off for the day at 7pm.
The pair will open play on the same court today and the delay could actually prove to be a blessing in disguise for top seed Nadal, whose last act before the rain was to leave the arena for a medical timeout.
He stumbled to the floor on the ninth point of the tie-break and took longer than usual to get up, although he sprinted off the court to suggest the problem may not be that serious and was last night seen walking out of the grounds showing no obvious signs of discomfort.