Brady threw for two second-half touchdowns and ran in his first rushing TD in almost three years after enduring five sacks in the first half, and the Patriots pulled away from a Dallas offense left powerless without Romo and star receiver Dez Bryant.
"Have you seen him play for the last 15 years?" receiver Julian Edelman, who had a 59-yard touchdown catch for a 27-6 lead early in the fourth quarter, said of Brady. "He's pretty tough. I don't think anyone underrates his toughness."
The Super Bowl champion Patriots (4-0) won their seventh straight game going back to the playoffs last year. The Cowboys (2-3) lost their third in a row without Romo and Bryant.
Coach Jason Garrett said the Cowboys would evaluate the quarterback spot during their upcoming bye after Brandon Weeden went 26 of 39 for 188 mostly meaningless yards. The Dallas running game also was mostly ineffective until it was too late.
Weeden's backup is now Matt Cassel, who used to be the No. 2 behind Brady in New England. Cassel was active for the first time since a trade with Buffalo on Sept. 22.
"I don't want to talk about it. I'm going to let my play do the talking," Weeden said. "I think that I played well coming into it. Those are their decisions. That's what their role is. My role is to play football and be ready."
While Romo can't return until the 10th game at the earliest, Bryant could be back for the Cowboys' next game in two weeks at the New York Giants.
Bryant had an injection last week to try to speed the healing of his broken right foot, an injury sustained in the season opener. Romo went down a week later.
"It would be a complete guess, but he certainly has the time for the bone to heal," owner Jerry Jones said.
Things to consider after Brady, in his 16th season, joined Peyton Manning and Fran Tarkenton as the only NFL quarterbacks with 4-0 starts at least four times:
GETTING TO BRADY: The 38-year-old hasn't been sacked more than five times in the regular season since Buffalo had seven in 2001, the year he took over as the starter and won the first of four Super Bowls.
The first two sacks came from linebacker Rolando McClain and defensive end Greg Hardy, both making their season debuts after four-game suspensions.
Hardy, who had a second sack that forced a fumble recovered for a short gain by the Patriots, made headlines during the week for commenting on Brady's supermodel wife, Gisele Bundchen, after being suspended because the NFL believed he roughed up his former girlfriend last year.
McClain, who was out for violating the league's substance-abuse policy, had the first sack.
"Those are two great players," said Brady, who threw for 275 yards, about 96 fewer than he averaged in the first three games for the league's No. 1 offense. "They add 'em to the mix and they've got a defense."
WOE IS WEEDEN: The third start in place of Romo was the roughest for Weeden, who has lost 11 straight as a starter going back to his time as a first-round draft pick in Cleveland. The Cowboys had just 59 yards at halftime, and trailed 20-3 before their first long drive, which ended with the second of their two field goals late in the third quarter.
SNEAKY: Brady's 1-yard sneak to put New England ahead for good in the second quarter was his first rushing TD since Dec. 16, 2012, when he had the last of his career-high four that season. It was the 15th of his career.
MISSING THE CENTURY MARK: The Cowboys are still without an individual 100-yard rusher after letting NFL rushing champion DeMarco Murray go to Philadelphia in free agency. It's the longest such drought to start the season for Dallas since 2005.
LONG KICK: New England's Stephen Gostkowski extended his NFL-best streak of made field goals to 19 with three, including a career-long of 57 yards in the final seconds of the first half. His previous long was 54.