Mayfield, who committed four turnovers, lost 45-42 to the Raiders in overtime.
The loss dropped the Browns to 1-2-1 and the victory improved the Raiders to 1-3.
Mayfield completed 21 of 41 attempts for 295 yards with two touchdowns and two interceptions for a 70.7 rating.
He rallied the Browns to a 42-34 lead in the fourth quarter, but was outplayed down the stretch by quarterback Derek Carr, whom the Browns passed on in the 2014 draft.
Carr tied the game at 42 on a 7-yard TD pass to Jared Cook with 30 second left in regulation, and then the Raiders won it 45-42 with 1:46 remaining on a 29-yard field goal by rookie kicker Matt McCrane.
The Browns trailed 34-28 with 10:46 left in regulation.
Mayfield had four turnovers, three that that led to Raiders' touchdowns. Oakland also had two big plays that led to Raiders' field goals, a 52-yard Marshawn Lynch run and a 49-yard punt return.
He had a pick-six, a strip-sack and a fumbled snap that all led to Raiders' TDs in regulation.
Mayfield, the 30th quarterback to start for the Browns since 1999, came through with a clutch 59-yard pass to fellow rookie Antonio Callaway, who got off to a horrible start, with 8:52 left in the game to the Raiders' 1. Carlos Hyde punched it in from the 1 to put the Browns up 35-34 with 8:07 remaining.
Nick Chubb then scored on his second long run of the game, a 41-yarder to give the Browns a little breathing room at 42-34 with 4:20 left. He had also scored on a 63-yarder in the second quarter.
But Derek Carr stormed backed and tied the game at 42 on the 7-yard touchdown pass to Cook with 30 seconds left, over Damarious Randall at the left side of the end zone. Jordy Nelson then caught the two-point pass over former Raider T.J. Carrie, also at the left side of the end zone, to tie it and send the Black Hole into a frenzy.
Mayfield had a chance to get the Browns at least in field goal range to win the game in regulation, but his pass for Antonio Callaway was picked off by Reggie Nelson with four seconds remaining.
The Raiders got the ball first in overtime, but Raiders' rookie kicker Matt McCrane's 50-yard field goal attempt with 6:10 left in overtime was short.
Mayfield went three-and-out on his first chance in OT, with Rashaan Melvin breaking up a deep ball down the right side to Duke Johnson.
The loss extended the Browns' road losing streak to 23 games.
Marshawn Lynch gashed for the Browns defense for almost 130 yards rushing.
Mayfield's fumbled snap
Mayfield was in the process of changing a play in the fourth quarter with the Browns clinging to a 28-24 lead when JC Tretter snapped the ball. Mayfield, not ready for the snap, fumbled it and former Buckeye Johnathan Hankins recovered. It was Hankins' second recovery of the game. Two plays later, Jordy Nelson caught a 19-yard TD pass from Carr that gave the Raiders a 31-28 lead.
The Browns continue to implode in the fourth quarter when Dwayne Harris returned a punt 49 yards to set up a 44-yard Matt McCrane field goal that extended the Raiders' lead to 34-28.
Rookie receiver Antonio Callaway then apparently fumbled on a punt return, but his knee was ruled down upon review.
Lynch's 52-yard blast
The Raiders closed to within 28-24 after Lynch ripped off a 52-yard run to the Browns' 17. But free safety Damarious Randall dropped Dwayne Harris for a 1-yard loss loss to forced the Raiders to settle for a 29-yard field goal.
Backed up into his own end, Mayfield was strip-sacked by Maurice Hurst and former Buckeye Johnathan Hankins recovered with 5:45 left in the third. Three plays later, Carr hit tight end Jared Cook with a 7-yard TD pass to cut the Raiders' deficit to 28-21 with 5:34 left in the third.
Mayfield's second TD pass
Mayfield threw his second career touchdown pass, a 2-yarder to Jarvis Landry, with 7:26 left in the third quarter to make it 28-14. Duke Johnson's two-point run was ruled good upon Browns' review. The score cashed in Randall's interception of a Carr pass intended for Martavis Bryant and 50-yard return.
Damarious Randall's INT
Randall's interception, the second of the game by the Browns, gave the Browns 13 takeaways on the season which equaled their total from all of last season. Randall swiped the pass and rumbled for 50 yards despite the fact he barely practiced all week with a heel injury and was listed as questionable.
Callaway's up and down day
Antonio Callaway's outing got off to a bad start but he recovered started early on and he never recovered. He slipped twice, including once on Gareon Conley's pick six that went off Callaway's hands. A streaking Callaway couldn't quite catch up to a Mayfield deep ball in the end zone, and then he dropped several passes, including a short out in the third quarter and a two-point pass.
Browns go up 20-14 on a FG
Rookie kicker Greg Joseph kicked his second field goal of the game, a 28-yarder, to increased the Browns lead to 20-14. Joseph also kicked a 25-yarder in the first quarter to make it 7-3.
Mayfield's first TD pass
Mayfield made his first TD pass a memorable one. With the Browns clinging to a 9-7 lead, Mayfield found 6-7 tight end Darren Fells singled up with 5-11 safety Reggie Nelson down the left side, and Fells rumbled 49-yards for the touchdown. Duke Johnson ran in on the left side of the end zone for the two-point conversion that increased the Browns' lead to 17-7 with 9:00 minutes left in the half. Mayfield has no qualms about throwing to covered receivers and tight ends, because he knows he can fit it into tight windows.
Mayfield's first pick-six
Mayfield experienced his first pick-six in the NFL on his second drive of the game, but it wasn't his fault. Antonio Callaway slipped coming out of his break, and the ball went off his hands. Former Buckeye Gareon Gonley, a native of Massillon, Ohio, picked it off and returned the ball 36 yards for a touchdown. That made it 7-0 Raiders with 10:01 left in the first quarter. It was the second time Callaway had slipped in the game, and he wasn't even on the infield dirt. Callaway had also slipped on the first play of the game when he went in motion
Mayfield goes three and out early
Mayfield went three-and-out on his opening drive after Jarvis Landry and Rashard Higgins dropped back-to-back passes. Landry caught the short pass but then couldn't hang on when linebacker Marquel Lee nailed him. Higgins flat-out dropped a right sideline pass.
Chubb's TD run
Rookie running back Nick Chubb, who came into the game with only seven carries for 41 yards, ripped off a 63-yard touchdown run with 12:35 left in the half to put the Browns on top 9-7. Callaway dropped the two-point pass in the end zone. Chubb's TD was the longest by a Browns rookie since Lee Suggs had a 78-yard score on Dec. 28, 2003.
Terrance Mitchell's injury
Mitchell, the Browns' starting cornerback, suffered what appears to be a serious right wrist injury when he broke up a second-quarter pass to Jordy Nelson. Mitchell immediately grabbed the wrist and went to the medical tent. He was carted off with a big air cast on the wrist and carted to the locker room. It was announced in the third quarter that he was out for the game.
E.J. Gaines’ INT
Gaines replaced Mitchell and picked off Carr with 23 seconds left in the half to prevent the Raiders from going ahead or tying the game at the break. The pass went off Cook's hands and Gaines was there to swipe it at the Browns' 15 when Carr was driving. It preserved the Browns' 17-14 lead at the half. The INT gave the Browns 12 takeaways on the season, their most through four games since 1989.
The Browns host the Ravens at 1 p.m. Sunday.