Daredevil's original costume, as designed by Jack Kirby was a combination of black, yellow and red, reminiscent of practical acrobat's tights, and went through minor revisions in issues #2 through #4 by EC Comics artist Joe Orlando. Fellow acclaimed EC veteran Wally Wood penciled #5-8, introducing the modern, completely red costume in issue #7. Golden Age great Bob Powell (Sheena, Queen of the Jungle) penciled two issues over Wood layouts, and they then swapped for #11, which Wood inked over Powell's pencils.

Issue #12 began a brief run by Jack Kirby (layouts) and John Romita, Sr. It was Romita's return to superhero penciling after a decade of working exclusively as a romance-comic artist for DC. Romita had felt he no longer wanted to pencil, in favor of being solely an inker.

When Romita left to take over Amazing Spider-Man, Lee gave Daredevil to the character's first signature artist, Gene Colan, who began with issue #20 (Sept. 1966). Colan pencilled all but three issues through #100 (June 1973), plus the 1967 annual, followed by ten issues sprinkled from 1974-79. (He would return again, an established legend, for an eight-issue run in 1997). Among the notable plot developments during this period were Matt Murdock's panicky creation of a "twin brother", the "sighted" and devil-may-care Mike Murdock, in #25 (Feb. 1967), whom Karen Page and Foggy Nelson are led to believe is Daredevil; "Mike's" death in #41 (June 1968); and Matt revealing his Daredevil identity to Karen Page in #57 (Oct. 1969).

Much like in The Amazing Spider-Man — and in what was already an established hallmark of Marvel Comics storytelling — interpersonal drama was as central to the series as action and adventure. A triangle of unrequited love develops between Foggy Nelson, Karen Page and Murdock, with Nelson unable to win over Page and Matt unable to admit that Page loves anyone other than Daredevil. When the revelation of Murdock's dual identity proves too much for Page, she leaves the firm and the comic.

In the 1970s the title featured a double billing, co-starring Daredevil's girlfriend, the Black Widow. During this time, the series' writers included Gerry Conway, Steve Gerber and Chris Claremont. Artists included Bob Brown and Don Heck.