Raul Jimenez continued his goalscoring form at the Estadio Rommel Fernandez Gutierrez, netting a brace.
Jimenez needed just eight minutes to score in Panama City before wrapping up Mexico's victory from the penalty spot after he had set up Edson Alvarez.
It marked Mexico's third win in as many games in Group B of League A as Gerardo Martino's men joined Honduras in the semi-finals.
Panama almost took a shock lead, Mexico goalkeeper Guillermo Ochoa making a low save to deny Gabriel Torres after an Alberto Quintero cross from the right.
However, Mexico opened the scoring as they dominated most of the first half.
In a move that started with Ochoa, Roberto Alvarado teed up Jimenez, who side-footed into the bottom corner from inside the area in the eighth minute.
Mexico had chances to double their lead in the opening 20 minutes, Alvarado and Jimenez squandering opportunities, the latter denied by Panama goalkeeper Jose Calderon.
The visitors continued to push for a second and they found it with 20 minutes remaining through Alvarez.
After a set-piece was partly cleared, Jimenez curled in a beautiful cross from the right for Alvarez to tuck in from close range.
Mexico were awarded a late penalty after Anibal Mello brought down substitute Uriel Antuna as the attacker ran onto a long pass.
Jimenez stepped up to convert the penalty, completing his brace and wrapping up a deserved win for Mexico.
What does it mean? Semi-final spot booked
Mexico moved into the semi-finals courtesy of their latest win. In a group featuring Panama and Bermuda, there was never any real doubt for Mexico, who will surely be hoping tougher tests await.
Jimenez stays hot
The Wolves forward is in form for club and country. Jimenez has now scored in six of his past seven games since mid-October, good signs for both Mexico and the Premier League club.
Is Nations League pointless for Mexico?
Mexico may be left wondering exactly what they can get out of the Nations League. Competitive against South American nations, Martino's men have been left to play both Panama and Bermuda twice due to the introduction of the Nations League in CONCACAF, rather than testing themselves against bigger countries.
Mexico finish their group-stage campaign at home to Bermuda on Tuesday, while Panama will next be in action in 2020.