Kruszelnicki attended high school at Edmund Rice College in Wollongong. He received a Bachelor of Science degree, majoring in physics and mathematics from the University of Wollongong. He completed a Master of Biomedical Engineering degree (MBiomedE) from the University of New South Wales and also received Bachelor of Medicine and Surgery degrees from the University of Sydney in 1986.

Kruszelnicki wrote and presented the first series of Quantum. He writes a weekly column for The Age and the Sydney Morning Herald newspapers on scientific "mythconceptions". His radio work includes a weekly science talkback show on Triple J which attracts up to 300,000 listeners and is available as a podcast. He often helps with other science and education Triple J promotions, such as the Sleek Geek Week roadshow with Adam Spencer and Caroline Pegram.

In the United Kingdom, he appears on a live weekly late-night link-up on BBC Radio 5 Live's Up All Night, usually with Rhod Sharp (Thursdays 03:00 UK time), answering science questions.

He has had cameo appearances in a number of television series including Pizza (screened on SBS) and Neighbours. In the Neighbours episode, he was confused with the Dr Karl character of that series. In early 2008 he co-hosted a TV series of Sleek Geeks with Adam Spencer.

Kruszelnicki fronts the Roads and Traffic Authority microsleep awareness campaign and presents segments on The Weather Channel.

Kruszelnicki was an unsuccessful candidate for the Australian Senate in the 2007 Australian federal election. He was placed number two on the Climate Change Coalition ticket in New South Wales.

One of Kruszelnicki's more notable undertakings was his part in a research project on belly button fluff, for which he received an Ig Nobel Prize in 2002. He received the Australian Father of the Year award in 2003. In the 2006 Honours list, he was made a Member of the Order of Australia.

, Kruszelnicki has written 27 books, along with numerous lecture series (utilising material that often ends up in his books, or vice versa). Some of these lecture series and books have been televised for events such as Science Week, with him supplying voice overs and sometimes appearing in claymation.

• Latest Great Moments in Science, Australian Broadcasting Corporation Enterprises, Sydney, Australia, ISBN 0-7333-0144-4
• Spacescape, Harcourt Brace Jovanovich, (Australia), 1992, ISBN 0729511006
• Absolutely Fabulos Moments in Science, Australian Broadcasting Corporation Enterprises, Sydney, Australia, 1994, ISBN 0-7333-0407-9
• Sensational Moments in Science, Australian Broadcasting Corporation Enterprises, Sydney, Australia, 1995, ISBN 0-7333-0456-7'
• Pigeon Poo the Universe & Car Paint - and other awesome science moments, HarperCollins Publishers Pty Ltd, Australia, 1996, ISBN 0-7322-5723-9
• Flying Lasers, Robofish and Cities of Slime - and other brain-bending science moments, HarperCollins Publishers Pty Ltd, Australia, 1997, ISBN 0-7322-5874-X
• Dr Karl's Collection of Great Australian Facts & Firsts

:1. Ears, Gears and Gadgets, HarperCollins Publishers Pty Ltd, Australia, 1997, ISBN 0-207-19610-9.

:2. Forests, Fleece & Prickly Pears, HarperCollins Publishers Pty Ltd, Australia, 1997, ISBN 0-207-19611-7

:3. Flight, Food & Thingummygigs, HarperCollins Publishers Pty Ltd, Australia, 1997, ISBN 0-207-19612-5.

• Munching Maggots, Noah's Flood and TV Heart Attacks and other cataclysmic science moments, HarperCollins Publishers Pty Ltd, Australia, 1998, ISBN 0-7322-5858-8.
• Fidgeting Fat, Exploding Meat & Gobbling Whirly Birds - New Moments 4, 1999.
• Q&A With Dr. K - Why It Is So. Headless Chickens, Bathroom Queues and Belly Button Blues, HarperCollins Publishers Pty Ltd, Australia, 2001, ISBN 0-7322-5855-3.
• Dr. Karl's Collection of Great Australian Facts & Firsts, HarperCollins Publishers Pty Ltd, Australia, 2002, ISBN 0-207-19860-8.
• Bumbreath, Botox and Bubbles and other Fully Sick Science Moments, HarperCollins Publishers Pty Ltd, Australia, 2003, ISBN 0-7322-6715-3.
• Great Mythconceptions - Cellulite, Camel Humps and Chocolate Zits, HarperCollins Publishers Pty Ltd, Australia, 2004, ISBN 0-7322-8062-1.
• Dis Information and Other Wikkid Myths: More Great Myths In Science, HarperCollins Publishers Pty Ltd, Australia, 2005, ISBN 0-7322-8060-5.
• It Ain't Necessarily So Bro, HarperCollins Publishers Pty Ltd, Australia, 2006, ISBN 0-7322-8061-3.
• Please Explain, HarperCollins Publishers Pty Ltd, Australia, 2007, ISBN 0-7322-8535-6.
• Science Is Golden, HarperCollins Publishers Pty Ltd, Australia 2008 ISBN 0-7332-8536-4.
• Never Mind the Bullocks, Here's the Science, HarperCollins Publishers Pty Ltd, Australia 2009, ISBN 0-7322-8537-2.
• Dinosaurs Aren't Dead, Pan Macmillan Pty Limited, Australia 2010