Droylsden were originally formed at the invitation of Joseph Cropper, the landlord of the Butchers Arms public house, to play behind the pub. After twenty years of friendlies and local leagues, disbandment, reformations and changes of strip, the club emerged from World War I the sole survivors amongst the village teams, and as members of the Manchester League.

The club also adopted their now traditional colours of red and white, the inspiration for the unusual nickname of The Bloods.

Two games in the 1921 Manchester Junior Cup Final against Hyde United who were in the Manchester Football League attracted over 1,500 fans to see Hyde prevail. However, the Bloods had their revenge two years later, taking the Cup from their local rivals.

The 1930s was the era of Droylsden's record goal scorer, Ernest "Gilly" Gillibrand, scorer of 275 goals in just four seasons. Gilly's goals saw Droylsden to the Manchester League Championship in 1931 and again in 1933, and in the latter season he aided Droylsden to the Third Qualifying Round in their first season in the FA Cup.

In 1936, the club successfully applied to join the Lancashire Combination and, a season later, became a nursery club to Manchster City, whose A team played at the Butchers Arms. Also their surplus players were available to Droylsden, who were then disqualified from the FA Cup.

When other competitions were suspended in 1939 at the start of World War II, Droylsden entered the Cheshire League, reaching their highest ever league position as runners-up in their second season in 1945-46. However, the club couldn't build on that start and, four seasons later, failed in their second successive bid for re-election. Worse was to come with the sale of the Butchers Arms lease to Belle Vue FC, who renamed themselves Droylsden United. All of which meant that the Bloods were forced out to the nearby Moorside Trotting Stadium. The town wasn't big enough for two clubs, especially with bad feeling between them, and after the local council bought the ground, a merger was negotiated.

Droylsden came home in 1952 to a renovated ground whose pitch had been rotated to its present position, finally eradicating a long-standing drainage problem.

Two decades in the Combination ended in 1968 with a return to the Cheshire League, after the formation of the Northern Premier League. The club won the Manchester Senior Cup in 1973, 1976 and 1979 and enjoyed some FA Cup success, reaching the Fourth Qualifying Round four times in five seasons and the Cup proper twice.

In 1976 Droylsden lost 5-3 in a First round replay at Grimsby Town, after a late home goal was disallowed. In 1978, Dave Taylor's goal at Rochdale sent Drolysden through to a second round tie at home to Altrincham, who ended the run with a 2-0 win. However when the late 1970s side broke up, Droylsden's fortunes slumped, and they finished a distant bottom of the First Division in 1982. They were then placed in Division Two of the new North West Counties Football League. The unstable period ended with the appointment of Mark Fallon as player-manager. In his second season Fallon guided the club to the Second Division Championship, which was Droylsden's first senior honour.

After finishing third in the inaugural season of the Conference North in 2004-05, Droylsden were looking to go one better and reach the top tier of non-league football for the first time in their history. A fourth-place finish in the 2005-06 season gave Droylsden a second chance to reach the Conference National through the play-offs. However, they narrowly missed out on promotion in a penalty shoot-out in the final against Stafford Rangers.

On 29 March 2006 Droylsden lost 2-1 to Hyde United in the final of the Manchester Premier Cup. On 18 April 2007 they beat Flixton 3-0 in the final of the Manchester Premier Cup. Three days later they beat Harrogate Town 2-0 and so won promotion to the Conference National as Conference North champions with two games in hand. However, they struggled in the Conference National, and were relegated back to the Conference North on 8 April even though they beat Farsley Celtic 2-1, due to Weymouth's draw against Grays Athletic the same evening.

A return to the blue square north in the 2008/09 season saw Droylsden finish seventh with an almost completely rebuilt squad. Winners of the Manchester cup and a long unbeaten run in the FA cup, only to be disqualified for an administration error regarding an ineligible player.