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Initially formed by Irish students, Salamanca first played in early Spanish championships in 1907, before an official league was founded later on. On 16 March 1923, at the tables of Café Novelty, situated in the Plaza Mayor, Dionisio Ridruejo set the club's early official foundations and, from 1939 and during the following three decades, it fluctuated between the third and the second levels of the Spanish football league.

In the 1974–75 season, Salamanca made its La Liga debuts, overachieving for a final 7th position (out of 18 teams), which eventually would be its best classification ever. The team lasted in the topflight until 1981, mainly coached by José Luis García Traid, then returned the following year for a further two seasons, being further relegated to Segunda División B – the new third division created in 1977 – in 1984–85, and spending three years in that category before promoting back.

In 1994–95's second division, after finishing fourth in the league, Salamanca lost the first leg of the promotion/relegation playoffs against Albacete Balompié, 0–2 at home, but won 5–0 away, returning to the main level after eleven years. The club was managed by 29-year-old Juan Manuel Lillo, also in charge for the following season, as the Castile and León club ranked 22nd and last in the top level.

From 1999 onwards (with two more visits to the first division, with 15th and 20th-place finishes respectively), Salamanca stabilized in the second level, save for the 2005–06 season spent in the third division, with the club winning the regular season and promoting in the playoffs. Veteran Quique Martín was arguably the most important player of the club in the decade, whilst Argentine Jorge D'Alessandro, who held the record for most games in the top division in the club's history, worked with the team as a manager in a further two spells (three in total).

2010–11 brought a club record ten consecutive defeats between December 2010/February 2011, and two coaching changes, as Salamanca returned to the third division after five years. On 18 June 2013, 90 years after its foundation, the club was liquidated due to the accumulation of unpaid debts.