Sentinel Comics began publishing Mystery Comics in August of 1946 as a title centered, given the name, on mysteries. The other notable titles that preceded it were the superheroics of Legacy over in Justice Comics and the outer-space adventures of Cosmic Tales, so this filled a slightly more grounded niche.
Its first issue introduced the Scholar, who would continue to appear in supporting roles throughout the Multiverse Era of Sentinel Comics publishing, but it wasn't until issue #27 in October 1948 that the breakout character was introduced who would have a more permanent association with the title - the Wraith. Her street-level vigilantism in crime-ridden Rook City would serve as a contrast in approach to heroics with Legacy and would come to define the feel of the book.
The 1970s was a period when a lot of the background details were presented for the first time (e.g. the concept of "Rook City" and just how bad things were there as opposed to the generic crime-filled city it had been up to this point), a lot of readers were also dissatisfied with the drift away from Wraith's stories in particular. As a result, the title was reorganized in a second volume in May 1980 (the April issue #405 being the last of the first volume). Volume 2 would become a twice-a-month title with one Wraith-centric issue and one about assorted other Rook City stories. This setup continues until December 1986 with issues #159 and #160. Starting in January 1987 it's back to being only one issue a month, once again mainly being stories involving Wraith's solo adventures. When the Multiverse Era ends after the OblivAeon event, volume 2 had reached #523. Due to this oddity of having twice-a-month issues, this means that Mystery Comics actually beats out both Justice Comics and Freedom Five for one of the long-running records: most issues produced with 928 in all over its two volumes.
#1 August 1946 - First appearance of the Scholar.
#27 October 1948 - First appearance of the Wraith.
#65 December 1951 - First appearance of the burglar and common Wraith nemesis, Ermine.
#98 September 1954 - First appearance of Maniac Jack.
#106 May 1955 - "Graduation Day" story when Maia Montgomery graduates college but is then handed control of Montgomery Industries from her parents.
#113 December 1955 - A slice-of-life where we get to know Maia in her post-college life, home alone for the holidays with her black cat, Shadow.
#191 June 1962 - First appearance of Tony Taurus, a supporting cast member for Wraith's stories. Part of the trend of fleshing out the setting that would become known as Rook City.
#214 May 1964 - First appearance of the villain Spite.
#338 September 1974 - First appearance of Fanatic, who is not really on-brand for the kinds of stories Mystery Comics was known for. This kind of trend away from Wraith is what prompts the second volume in a few years.
#405 April 1980 - Final issue of Volume 1.
#1 May 1980 - title becomes twice-a-month.
#21 March 1981 - First appearance of Expatriette. She becomes something of a headliner for about a year before getting a backstory.
#97 May 1984 - First appearance of Parse.
#98 May 1984 - Parse kills Spite as resolution of the major arc that had begun a few months prior.
#99 June 1984 - Wraith and Parse fight because Parse killed Spite.
#100 June 1984 - Conclusion of Wraith/Parse fight with the latter escaping.
#109 November 1984 - Parse takes on a drug-dealing gang. First appearance of Deion "Lefty" Young, who would become something of a supporting cast member as an unwilling informant for her. (Writer's Room #13, Episode 135, cover)
#145 May 1986 First appearance of Mr. Fixer (or rather, first time in that identity as he's a reimagining of the earlier hero known as Black Fist). Already actively fighting general crime and the forces of Zhu Long in Rook City.
#161 January - Title becomes once-a-month again.
#212 April 1991 - First appearance of Setback.
#289 September 1997 - Mystery Comics entry in the "death of Mr. Fixer" event that crossed over with several titles.
#290 October 1997 - First appearance of Kismet.
#291 November 1997 - Kismet story continues - Crosses over with the Run of Luck limited series that started this month.
#292 December 1997 - Kismet story continues - Crosses over with the Run of Luck limited series.
#479 July 2013 - NightMist banishes Bugbear outside of reality.
#482 October 2013 - First appearance of Ansel G. Moreau as the hero Stuntman.
#523 March 2017 - Final issue.