Shane Long was the only holdover from the side that beat Switzerland 1-0 at the Aviva Stadium on Friday, while Napoli midfielder Marek Hamsik and Liverpool defender Martin Skrtel were two of just three players to keep their place for the visitors.
Slovakia, who will face both England and Wales alongside Russia in Group B at the European Championship, grabbed a 14th-minute lead when Miroslav Stoch fired home Erik Sabo's cross.
To add insult to injury, goalkeeper Rob Elliot was stretchered off with a knee injury after appearing to catch his studs in the turf, delivering a potentially cruel blow to both his Euro hopes and Newcastle's bid to avoid relegation from the Premier League.
Ireland, though, responded seven minutes later after Long went to ground in a challenge with Slovakia keeper Matus Kozacik, with the Southampton striker tucking away the resulting spot-kick.
And Long won a second penalty within three minutes after he was upended by Skrtel, but this time he gave way to James McClean who beat Kozacik to put Martin O'Neill's side 2-1 in front.
However, McShane, who endured a torrid evening in his first international start in almost three years, handed Slovakia an equaliser in first-half stoppage time when he turned in Peter Pekarik's cross at the near post.
Ireland, who remain unbeaten in five meetings with Slovakia, will play the Netherlands on May 27 in Dublin then host Belarus in Cork four days later before travelling to France, where they have been drawn alongside Belgium, Italy and Sweden in Group E.