Humphries did not start as a Bobsledder but competed in alpine ski racing before the age of 16. After breaking both legs in separate crashes, she retired from the sport. In 2002 Humphries began her bobsleigh career as a brakeman, and was an alternate to the Canadian team at the 2006 Olympic Winter Games in Torino.

Humphries has competed since 2004 and currently slides with Phylicia George as her brakeman. She was married to Dan Humphries, a former Bobsledder who competed for Great Britain and Canada. However the pair divorced before the 2014 Olympics and Kaillie may or may not return to her maiden name of Simundson.

In 2007, Humphries was placed low on the Canadian depth chart and did not feature at the 2006 Winter Olympics. In an effort to compete she considered representing the United Kingdom, the country of her then-fiance, Dan Humphries. Opting to remain with the Canadian team, she gained a spot on the roster after signing up for a bobsleigh driving school. She won the silver medal in the mixed bobsleigh-skeleton team event at the 2008 FIBT World Championships in Altenberg, Germany.

Humphries 2009-10 World Cup season prepared her for the first prominent achievement of her career—winning the gold medal in the Two-woman competition at the 2010 Winter Olympics, with her 2009-10 brakeman Heather Moyse. The silver medal was won by fellow Canadians Shelley-Ann Brown and Helen Upperton. It marked the first time of the 2010 Olympics that Canadians had won two medals in one event. The win completed a childhood dream for Humphries. After the final run she said that "I don't think I can put it into words yet, we did our job, you know. The goal I set as a little kid, to have done it, is amazing."

After the 2010 Olympic win, Humphries met with less success on the World Cup tour and in World Championship competition for nearly two seasons. She only finished on the podium once during the 2010–11 World Cup season, though her consistent top-10 finishes allowed her to finish in third place for the overall season. Humphries slid to fifth place for the overall 2011–12 World Cup season, though she did have four podium finishes, including three gold medals, by the end of the season.

The "I've Been Bullied" campaign warns people of the long-term effects of bullying. She speaks about her personal experience as a victim of bullying, and she discusses the importance of avoiding bullying in any Sports. "Right to Play" is an organization that uses sport and play as a way to "educate and empower" children facing difficulties such as disease and conflict. She is in this organization with the other Canadian Olympic gold medallist, Gymnast Kyle Shewfelt. Humphries and Shewfelt brought equipment for Sports and set up some Sports programs for the underprivileged children and youth when Humphries and Shewfelt traveled to Liberia in April 2011. They want to give some of the children a chance to change their lives. In the Special Olympics, Humphries speaks regularly at a few elementary schools at Calgary about the importance of physical activity, setting goals, and saying "no" to drugs.

Humphries' success in the winter of 2012-13 included a repeat as World Champion, placing first while setting a track record at the 2013 FIBT World Championship race in St. Moritz. This win meant that Humphries finished on the podium in all 10 FIBT races during 2012-13, while extending her consecutive FIBT podium finishes to 13 when counting the last two races of the 2011–12 World Cup season plus the 2012 FIBT World Championship race. This streak of 13 consecutive podiums over two seasons included a run of eight consecutive wins from the end of 2011–12 through the start of 2012–13, while teamed with three different brakemen (Baadsvik for one win, Ciochetti for two wins and Valois for six wins/ten podiums).

This close 2013–14 contest between the Canadians and Americans carried into the 2014 Sochi Olympics competition. Meyers and Williams led after Day 1 of competition having produced two runs built on track record push starts that uncharacteristically beat out the Canadian team at what was their strong suit. Despite being beaten on the start times, Humphries made fewer driving errors and produced cleaner runs but was still just over two tenths of a second back from the lead time. On the second day of competition, the Americans again won out on quick starting pushes but made several driving errors on the technical course. Humphries' clean piloting propelled the Canadians from second place into the gold medal position, allowing them to become the first female bobsleigh team to repeat as Olympic champions, the first female Canadian Olympians to repeat as champions since Catriona Le May Doan, and etching their names into Olympic history. Humphries said of the record setting achievement: "How do you describe achieving a dream? This is a four-year goal of ours. This has been something that we've done together. Winning gold is amazing, but walking away satisfied is better. After the third run I knew that if we did the Business we could be on top."

Humphries won the 2014 Lou Marsh Award in December 2014 as Canada's top athlete for the year.

On January 9, 2016, Humphries became the first woman to drive an all-female team against men in a four-person World Cup bobsled race; her teammates were Cynthia Appiah, Genevieve Thibault and Melissa Lotholz. Although they finished last Humphries said the purpose was to help get a four-woman bobsleigh division added to the Olympics. Humphries knew their entry would not be a contender due to the 300 pound weight difference between her team and the all-men teams.