The best thing to do in Santa Fe is check out the historical religious sights which are abundant. The main attraction is definitely the Convento de San Francisco (San Martín and Amenábar, Tel. # 0342 4593303) which is an impressive feat of colonial architecture that also houses and interesting museum. The ceiling of the convent is especially amazing and a testament to the ingenuity of the pre Hispanic peoples who under gun point constructed the wooden masterpiece without using nails. Other highlights include the museum's collection of colonial pistols and swords and a recreation of the first signing of the Argentine constitution.
Also a chunk of door which bears the impressive claw marks of the mystical and mysterious "Santa Fe Tiger" that sprang out of the river and went on a rampage in town, killing four people before it was shot is on display. To this day no one knows where the creature came from (tigers are clearly not native to the province of Santa Fe). Across the plaza from the Convent is another museum, the Museo Historico Provincial, which has more colonial relics and a collection of traditional clothes and musical instruments.
Definitely check out the Recoleta area, where at night time everyone goes to let loose. Go get a drink, sample some of the local delicacies and try to find that tasty beer everyone is talking about!
Finally check out the beaches and try your hand at fishing in the Rio Paraná. The area around Santa Fe is known as a sport fishing paradise where trolling, fly fishing and spinning are all practiced by the nations professionals. For information on renting gear head to the tourist office.