Coming out of LSU, Reid was projected to be a first- or second-round pick by a majority of NFL draft experts and scouts. He received an invitation to the NFL combine and completed all of the required combine and positional drills. On March 27, 2013, he opted to participate at LSU's pro day, and chose to perform positional drills, the 40-yard dash (4.50), 20-yard dash (2.60), and 10-yard dash (1.54) for the scouts and team representatives in attendance. He was ranked the second best free safety in the draft by NFLDraftScout.com, the third best safety prospect by NFL analyst Mike Mayock, and the fourth best safety in the draft by Sports Illustrated.
The San Francisco 49ers selected Reid in the first round (18th overall) of the 2013 NFL Draft. In order to select Reid, the 49ers traded their first- (31st overall) and third-round picks (74th overall) in the 2013 NFL Draft to the Dallas Cowboys. He was the second safety selected behind Kenny Vaccaro (15th overall, Saints) and the second of six LSU players selected in the first three rounds, breaking the NFL draft record. A total of nine players from LSU were drafted in 2013, setting a new school record.
On July 5, 2013, the San Francisco 49ers signed Reid to a fully guaranteed four-year, $8.48 million contract that included a signing bonus of $4.54 million.
In Week 6, Reid collected three combined tackles, deflected a pass, recovered a fumble, and intercepted a pass attempt by Carson Palmer and returned it 53 yards, as the San Francisco 49ers defeated the Arizona Cardinals 32–20. On December 29, 2013, he earned a season-high ten combined tackles and defended a pass during the 49ers' 23–20 victory over the Arizona Cardinals. He finished his rookie season with 77 combined tackles (62 solo), 11 pass deflections, and four interceptions in 16 games and 16 starts. Reid was voted to be an alternate for the 2014 Pro Bowl.
The 49ers finished second in the NFC West with a 12–4 record under Jim Harbaugh in 2013. On January 5, 2014, Reid started in his first career playoff game and recorded nine combined tackles en route to a 23–20 victory over the Green Bay Packers in the NFC Wildcard game. On January 19, 2014, the 49ers played the Seattle Seahawks in the NFC Championship and Reid made four combined tackles in the 23–17 loss. On January 21, 2014, it was reported that Reid would be replacing Kam Chancellor in the 2014 Pro Bowl.