In his first college at bat, he launched a pinch hit grand slam to lift the Tigers to a victory over Mercer.

That, combined with Vargas' signing bonus demands, depressed his draft stock, so he went undrafted.

The tweak allowed Vargas to repeat his mechanics and keep his arm higher, which in turn increased the velocity on his fastball and improved the break on his curveball.

The new work ethic paid off, and in 2004 Vargas went 7–4 with a 4.14 ERA in 18 games on the mound, while hitting .354 with 14 doubles and five home runs as the team's designated hitter.

[4] The Florida Marlins drafted Vargas out of Long Beach State with their second-round pick in the 2004 MLB draft, and he was signed by scout Robby Cosaro; he was a collegiate teammate of Jered Weaver, who was the Anaheim Angels' first-round pick in 2004.

[4] He finished 2004 with three starts at the end of the 2004 campaign with one of the Marlins' Single-A affiliates, the Greensboro Grasshoppers of the South Atlantic League.

Vargas was then promising enough that Baseball America listed him 8th among the Marlins' top 10 prospects for 2005; those above him were Jeremy Hermida, Scott Olsen, Yorman Bazardo, Jason Stokes, Josh Willingham, Eric Reed, and Taylor Tankersley.

Vargas did start the 2005 season with Greensboro, as was expected, but he advanced quickly through the Marlins' minor-league system.

With his third club of the year, the Double-A Carolina Mudcats, he made three starts, going 1–0 with a 2.84 ERA and 25 strikeouts in 19 innings pitched.

He made his major-league debut on July 14, 2005, the same day on which the Marlins designated veteran starter Al Leiter for assignment.

Unlike Kensing, Olsen, and Bazardo, Vargas enjoyed nearly immediate success upon his arrival in the major leagues, and after Ismael Valdéz returned from a leg injury, the Marlins moved Brian Moehler to the bullpen and left Vargas in their rotation.

On August 21, Vargas started against the Dodgers and pitched his first complete game in the majors, giving up one run on six hits and striking out seven.

In his fourth appearance out of the bullpen, he allowed eight runs (seven earned) over 31⁄3 innings; the Marlins optioned him to the Triple-A Albuquerque Isotopes on May 14.

Vargas continued to struggle in his second stint with Albuquerque, allowing 38 earned runs on 56 hits in 311⁄3 innings.

Vargas began the 2007 season with the Triple-A New Orleans Zephyrs, compiling a 2–3 record with a 5.30 ERA, which Mets manager Willie Randolph described as "so-so".

[10] He was called up to the Mets on May 13 after an injured Moisés Alou was sent to the disabled list, and took over the rotation spot previously held by Mike Pelfrey, who was optioned to New Orleans after posting an 0–5 record in 6 outings.

[13] Vargas was optioned down to the Triple-A Tacoma Rainiers on July 7, 2009, to make roster room for Chris Shelton.

By the end of the season Vargas had thrown 192 innings over 31 starts, and posted a 9–12 record with a 3.78 ERA and 116 strikeouts.

In July, Vargas went 5–0 in six starts, had an AL-best 1.64 ERA, and was named the AL Pitcher of the Month.

[17] He opened the 2014 season as the number three starter for the Royals and posted a career-best 3.71 ERA over 187 innings, as he was 11–10 in 30 starts.

[7] On June 23, 2019, Vargas threatened a Newsday reporter with bodily harm (i.e., being punched out) in the Mets locker room after a game against the Cubs.

[7] On July 29, 2019, the Mets traded Vargas and $2.9 million to the Philadelphia Phillies for Double-A minor league catcher Austin Bossart.