Born in Cologne, Frodeno started out as a swimmer in South Africa at the age of 15, and he entered triathlon in 2000. He then went to Germany to compete in the Triathlon-Bundesliga, and qualified for the national team in 2002. As part of the national team he trained at the Olympic Training Centre in Saarbrücken. Before his Olympic victory, his best result was placing sixth in the 2007 World Championships, and winning the German Championship the same year. He had previously also placed second and third in various races of the World Cup from 2005 to 2008.
Frodeno's gold medal win at the 2008 Summer Olympics was a surprise. He beat the 2000 Olympic champion Simon Whitfield in a sprint finish, while the hot pre-race favorite and 2008 World Champion Javier Gómez finished in fourth place. The victory came the day after his twenty-seventh birthday. Frodeno continued to perform strongly in 2009 and 2010, finishing 4th overall in the World Championship Triathlon Series both years. He was on course to become World Champion in 2010, needing only a 4th place in the Series Grand Final in Budapest, but due to an injury struggled to a 41st-place finish, losing the Overall title to Javier Gómez.
Frodeno returned to the Olympics in 2012 to compete in the men's triathlon event where he would finish 6th. The next year, in 2013, he retired from the shorter standard and sprint triathlon after winning a gold medal as part of the German team in the mixed relay triathlon world championships in Hamburg. He subsequently switched to longer distance endurance triathlons, finishing second at the 2013 Ironman 70.3 European Championships in Wiesbaden and scoring his first Ironman 70.3 win at the 2014 Asia-Pacific Championship in Auckland. He finished third on his full-length Ironman debut at the Ironman European Championship and also finished third at the 2014 Ironman World Championship on his World Championship debut.
In 2015 Frodeno suffered a cycling injury that took him out of the inaugural Challenge Dubai. Instead he made his season debut at Ironman 70.3 Oceanside, winning the event while edging out Andy Potts and Lionel Sanders. Following Oceanside, Frodeno took 2nd at Cannes Triathlon and 1st at Ironman 70.3 Barcelona. He went on to win the Ironman European Championship on home soil in Frankfurt, winning with a lead of over ten minutes and breaking the course record by over five minutes. He won the 2015 Ironman 70.3 World Championship defeating Sebastian Kienle and the defending champion Javier Gomez.
On October 10, 2015, he made history, becoming the first triathlete, male or female, to win both the Olympic Triathlon Gold and the Ironman World Championship title. He won over a field that included defending champion Kienle, 2013 champion Frederik Van Lierde, Andy Potts, and Andreas Raelert. He began with a strong swim where he exited and transitioned onto the bike along with Potts and Dylan McNeice at the front, pulling away from the other leaders on the bike, and completing with one of the fastest marathon runs of the day.
On July 17, 2016 in Roth Germany, he improved the world record for the long distance by more than 5 minutes to 7:35:39 hours. The previous record was held by Andreas Raelert. His split times were 45:22 minutes swim, 4:09:22 hours bike and 2:40:35 hours for the marathon.
He won his second Ironman World Championship in October 2016, pulling away from 2014 champion and countryman Sebastian Kienle early on the run. Like in his 2015 victory he did not produce the races fastest split in any portion of the race but was very solid throughout. With Patrick Lange taking 3rd place, it was the first sweep by a country since 1997, when Germany also managed the feat with Thomas Hellriegel, Jürgen Zäck, and Lothar Leder.
Frodeno is married to Emma Snowsill, the gold medalist in women's triathlon at the 2008 Summer Olympics.