The Cymru Alliance was hit with an eve-of-season withdrawal, for the third successive campaign, following the departures of Penrhyncoch and Mostyn:
Rhydymwyn withdrew their membership, just four days before the start of the new term, citing a shortage of players to field a team in their opening fixture. The Vicarage Road club decided to rebuild their squad in the Clwyd League Premier Division instead.
Caernarfon Town managed to bounce back from their relegation, as they headed the Cymru Alliance table at the beginning of 2001, from Welshpool Town and Cemaes Bay. Llangefni Town, in their second season in the league, had games in hand on the leaders and were set fair for the remainder of the campaign. By March 2001, foot-and-mouth disease had impacted on Wales and the football season in many regions, with clubs in rural areas particularly affected. Nine fixtures in the Cymru Alliance were not played, by the conclusion of the 2000/01 campaign, but it did not prevent Caernarfon Town from making a swift return to the League of Wales. The Canaries finished eleven points ahead of Llangefni Town, who were unable to play two of their fixtures, with Welshpool Town and Cemaes Bay finishing behind the Lon Talwrn club.
The Oval club completed a memorable treble when they defeated Welshpool Town in the League Cup final and Holyhead Hotspur in the North Wales Coast Challenge Cup final. Buckley Town beat Lex XI in the North East Wales Challenge Cup final, whilst Welshpool Town completed a hat-trick of Central Wales Challenge Cup successes when they overcame Aberystwyth Town Reserves in the final. The Lilywhites were unable to make it a double, as they went down to Caersws in the Central Wales Senior Cup final, but the Maesydre club reached the last sixteen of the Welsh Cup, going out at the hands of Aberystwyth Town.
Whilst Caernarfon Town made a quick return to the League of Wales, there was no demotion from the Cymru Alliance, because no northern club was demoted from the top flight in 2001/02, whilst Anglesey rivals Glantraeth and Llangefni Town merged their resources to form a single club. With the league already one short of its full complement, the Cymru Alliance welcomed Gresford Athletic, Guilsfield and Llanfairpwll on promotion from the 3 feeder competitions.
Unusually, Guilsfield were elevated despite not finishing in the top two of the Mid Wales League, as this competition did not complete its fixtures due to the impact of foot-and-mouth. After concluding the first half of their fixture list, Welshpool headed the table, after going close in the previous two campaigns. Llangefni-Glantraeth were just 4 points behind the mid Wales club, despite playing two more games, whilst Porthmadog and Ruthin Town were handily placed with a game in hand on the leaders. As the campaign moved into the spring, Welshpool Town maintained their drive towards the championship with their nearest rivals being the Ynys Mon duo of Llangefni-Glantraeth and Cemaes Bay. At the conclusion of the season, the Lilywhites landed their first Cymru Alliance title by a 5 point margin over Llangefni-Glantraeth and with just four league defeats throughout the campaign.
Cemaes Bay held on for third place, for a second time in three seasons, from Porthmadog and Buckley Town , who appeared to be a club that was ‘on the up'. The Maesydre outfit completed a double when they lifted the Central Wales Challenge Cup for a fourth successive time, with victory over Mid Wales League opponents Kerry in the final. Welshpool managed to reach the quarter finals of the Welsh Cup before bowing out 4-0 to the Flexsys Cefn Druids team that had overcome Halkyn United in the previous round.
Elsewhere Cemaes Bay ended the 2001/02 season by lifting the league cup with victory over Ruthin Town in the final. The Parc-y-Dre outfit also lost to Buckley Town in the final of the NE Wales Challenge Cup