Span scored from second on a single by Orlando Cabrera when the throw from center fielder Marlon Byrd beat him to home plate but slipped between Rodriguez's legs. The 13-time Gold Glove winner was making his first start for the Rangers since the final game of the 2002 season.
The Twins rallied from a 4-0 deficit the night after ruining the 14-time All-Star catcher's arrival in a trade from Houston by coming back from 5-0 down. The rally also spoiled Rodriguez's three-hit night.
The Rangers fell a game behind Boston in the AL wild-card race.
Scott Baker (11-7) escaped trouble three times to keep the Twins close. He gave up nine hits and four runs and struck out six in 5 1-3 innings.
After Rodriguez started a string of four straight singles that gave the Rangers a 3-0 lead in the third, Baker settled down and retired the heart of the Rangers lineup in order.
Rodriguez's double in the fourth gave Texas a 4-0 lead and put runners at second and third with no outs. Two infield groundballs and a strikeout later, Baker was out of trouble again. In the fifth, Baker escaped a one-out triple by Hank Blalock with strikeouts of David Murphy and Ian Kinsler.
Baker's resilience paid off in the sixth, which started with consecutive doubles from Michael Cuddyer and Joe Crede. After Rangers starter Kevin Millwood got two outs, No. 9 hitter Nick Punto reached base for the third straight time with a single that scored Crede to make it 4-3. Span's double scored Punto to tie it.
The Twins wiped out a Texas lead with a four-run sixth for the second night in a row. As a result, Millwood (9-8) fell to 0-7 lifetime against the Twins.
Jose Mijares pitched 2 2-3 hitless innings to protect Minnesota's one-run lead, and Joe Nathan pitched a perfect ninth for his 31st save and second in two games after going all of August without a save chance.
Fans, including one displaying a sign that said "We missed you Pudge," cheered wildly all night for Rodriguez, who played the first 11 seasons of his career with the Rangers.
The crowd had barely settled from a standing ovation before Rodriguez's first at-bat when he singled on a grounder up the middle leading off the third inning. Rodriguez went to third on a single by Elvis Andrus and scored on Julio Borbon's bloop single. Michael Young followed with a two-run single to right, giving the Rangers a 3-0 lead.
Rodriguez was challenged defensively on tough back-to-back plays in the top of the third. He made the first, jumping up to grab a slow roller by Delmon Young on the first-base foul line and making the throw with Young blocking his view. Carlos Gomez followed with a bunt that was ruled a single after Rodriguez couldn't make the barehand pickup.
NOTES: Twins 1B Jason Morneau missed his second straight start with recurring dizziness stemming from an inner ear infection. Morneau continues to take medication and is day to day. … DH Jason Kubel was in the Twins lineup despite a bruised left knee sustained when he fouled a ball off his leg in the first inning of Tuesday night's game. … The Rangers put LHP Eddie Guardado on the disabled list with left knee inflammation and recalled RHP Willie Eyre from Triple-A Oklahoma City. The Guardado move was retroactive to Saturday. … Entering Wednesday, OF Borbon and SS Andrus of the Rangers were the only major league players with multiple three-steal games.