Contesting his first stage race of the year, the 34-year-old Australian capitalised on strong support from his BMC team-mates, particularly American workhorse George Hincapie, to improve from second overall to race leader with two days left.
Evans led by just two seconds from Ivan Basso, with two more leading Italians, Damiano Cunego (3s) and Michele Scarponi (5s), also on his hammer.
Previous race leader Robert Gesink of the Netherlands was dropped on the final climb and fell to fifth overall, also at 5s.
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But if Evans can retain the lead through the 178km stage six, the 2009 world champion will be in the box seat for victory with only a 9.3km individual time trial remaining.
He looks the best time triallist among the overall contenders.
The two-time Tour de France runner-up thrived in the rain and cold of the race's longest leg - a hilly 240km haul from Chieti to Castelraimondo - and he regretted making a "nice stuff up" when looking a good chance to snatch the stage win.
He had to settle for 12th place, two seconds behind former team-mate Philippe Gilbert of Belgium who stormed home to snatch victory on the line.
"I really don't think on a finish like that I'm going to be able to beat Gilbert," he said.
"I got caught back in traffic and couldn't get anywhere in the finish, which is a bit disappointing.
"But for the GC, it was reasonably successful."
Evans is starting the season much later than normal as he builds up towards July's Tour de France.
He was unsure about his prospects of retaining the lead for the next two days.
"There's still another tough stage to come and anything can happen," he said.
"Then we've got the final time trial, which is very important.
"Such a short and intense time trial is very difficult after three hard days - it's difficult to go well and so a lot of things can still happen."
Gilbert stunned Wout Poels in a sprint finish after his Dutch rival had chased down a two-man breakaway, with Cunego coming in third.
Evans said he would continue to rely on teamwork, which was a big feature of his strong stage five result.
He noted how well Hincapie performed on Sasso Tetto, the major climb of the day.
"(Team) Lampre rode a good tempo and then actually George nearly `rode' the entire second half of the climb," Evans said.
"He's riding really well. There were a few people close on GC (general classification, or overall) that we were always preferring to eliminate, so that was a good move by George."
